Thienopyridines

FIELD: chemistry.

SUBSTANCE: invention relates to pharmaceutically suitable salts which are given in claim 1. The invention also relates to medicinal agents based on the said compounds, which are HSP90 inhibitors.

EFFECT: novel compounds and medicinal agents based on said compounds are obtained, which can be used to treat diseases influenced by inhibition, regulation or modulation of HSP90.

3 cl, 1 tbl, 16 ex

 

Background of invention

The object of the invention is the identification of new compounds having valuable properties, in particular those that can be applied to obtain drugs.

The present invention relates to compounds that are involved in the inhibition, regulation and/or modulation of HSP90, furthermore to pharmaceutical compositions which contain these compounds and to the use of compounds for the treatment of diseases involving HSP90.

Proper packing and conformation of proteins in cells is provided by molecular chaperones and is extremely important for the regulation of the balance between synthesis and degradation of proteins. Chaperones are important for the regulation of many major functions in cells, such as cell proliferation and apoptosis (Jolly and Morimoto, 2000; Smith and others, 1998; Smith, 2001).

Heat shock proteins (HSP)

Cells in the tissue to respond to external stresses, such as, for example, heat, hypoxia, oxidative stress or toxic substances such as heavy metals or alcohols, by activating many chaperones, which are known under the term "heat shock proteins" (HSP).

Activation of HSP proteins in the cells if the damage is initiated such stressors, accelerates restoration of the physiological state and leads to stresstolerant state in the cell. In addition to initially open protective mechanism against external stress, mediated HSP, in the future were also described other important functions of chaperones to specific HSP in normal conditions without stress. Thus, various HSP regulate, for example, proper stacking, intracellular localization and the function or variable collapse of many biologically important proteins in the cells.

HSP form a family of genes with a separate gene products with which different cellular expression, function and localization in different cells. Name and classification within this family is based on their molecular weight, such as HSP27, HSP70 and HSP90.

Cause some human diseases is improper installation of proteins (for review see, for example, Tytell and others, 2001; Smith and others, 1998). Therefore, in such cases will be suitable for development of therapeutic approaches based on the mechanism of chaperone-dependent stacking of proteins. For example, incorrect laying of proteins leads to protein aggregation with neurodegenerative progression in the case of Alzheimer's disease, prion disease or syndrome Huntington. Improper installation of proteins can also lead to loss of function of wild-type, due to what can happen improper regulation of molecular and f is zoologicheskoi functions.

HSP also attributed importance in neoplastic diseases. The obtained data indicate that, for example, the expression of certain HSP correlates with the stage of progression of tumors (Martin and others, 2000; Conroy and others, 1996; Kawanishi and others, 1999; Jameel and others, 1992; Hoang and others, 2000; Lebeau and others, 1991).

The fact that HSP90 is involved in many Central oncogenic pathways signaling in cells and certain natural products with anticancer activity aimed at HSP90 led to the emergence of the concept that inhibition of HSP90 functioning should be useful in the treatment of neoplastic diseases. In the present clinical study is the HSP90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17AAG), derived geldanamycin.

HSP90

HSP90 is about 1-2% of the total mass of proteins in the cell. Usually it is in the form of a dimer in the cell and is associated with many proteins, so-called co-chaperones (see, for example, Pratt, 1997). HSP90 is essential for the viability of the cells (Young and others, 2001) and plays a crucial role in the response to cellular stress by interacting with many proteins, native styling which is modified due to external stress, such as heat shock, to restore the original setting or prevent the aggregation of proteins (Smith and others, 1998).

The obtained t is the train data, indicate that HSP90 is important as a buffer against the action of mutations, presumably, by correcting the incorrect stacking of proteins, caused by a mutation (Rutherford and Lindquist, 1998).

Additionally, HSP90 is also important regulatory. In physiological conditions, HSP90, together with its homologue in the endoplasmic reticulum GRP94, takes part in the cellular balance to ensure the stability of the conformation and maturation of various interrelated with them the key proteins. They can be divided into three groups: steroid hormone receptors, Ser/Thr or tyrosine kinases (e.g., ERBB2, RAF-1, CDK4, and LCK) and a set of different proteins, such as, for example, mutated p53 or the catalytic subunit of telomerase hTPET. Each of these proteins is essential for the regulation of physiological and biochemical processes in cells. Fixed HSP90 family in humans consists of four genes, cytosolic HSP90α, the inducible isoform of HSP90β (Hickey and others, 1989), GRP94 in the endoplasmic reticulum (Argon and others, 1999) and HSP75/TRAP1 in the mitochondrial matrix (Felts and others, 2000). Assume that all members of this family have the same way of action, however, depending on their localization in the cell, associated with a variety of accompanying proteins. For example, ERBB2 is specific related protein d is I GRP94 (Argon, etc., 1999), while discovered that the receptor 1 type of tumor necrosis factor (TNFR1) or retinoblastoma protein (Rb) are interconnected with TRAP1 (Song and others, 1995; hen and others, 1996).

HSP90 is involved in various complex interaction with a large number of related proteins and regulatory proteins (Smith, 2001). Although the exact molecular data are still not installed, using biochemical experiments and research by crystallographic analysis with x-rays in recent years has increased the possibility to decipher the details of the functioning of the chaperone HSP90 (Prodromou and others, 1997; Stebbins and others, 1997). Therefore, HSP90 is an ATP-dependent molecular chaperone (Prodromou and others, 1997)dimerization, which is essential for ATP hydrolysis. Binding of ATP leads to the formation of toroidal dimeric structure, in which two N-terminal domain are in close contact with each other and act as a switch in conformation (Prodromou and Pearl, 2000).

Known inhibitors of HSP90

First open class of HSP90 inhibitors were benzophenone ansamycin connections herbimycin and geldanamycin. Originally they were identified by the reversion of malignant phenotype in fibroblasts, which is induced by transformation with v-Src oncogene (Uehara and others, 1985).

It was later while the ANO a strong antitumor effect in vitro (Schulte and others, 1998) and in animal models in vivo (Supko and others, 1995).

Then when holding immune precipitation and research on affine matrices, it was shown that the main mechanism of action geldanamycin involved in binding to HSP90 (Whitesell and others, 1994; Schulte and Neckers, 1998). Additionally, when conducting crystallographic analysis with x-rays was shown that geldanamycin competes for the ATP-binding site and inhibits internal ATP-asnow activity of HSP90 (Prodromou and others, 1997; Panaretou and others, 1998). This prevents the formation of multimeric HSP90 complex, which functions as a chaperone for related proteins. As a consequence, related proteins are broken down by the ubiquitin-proteasome mechanism.

Derived geldanamycin, 17 allylamino-17-demethoxygeldanamycin (17AAG), shows an unmodified properties in the inhibition of HSP90, degradation related proteins and anti-tumor activity in cell cultures and on models xenotransplantion tumors in mice (Schulte and others 1998; Kelland and others 1999), but has significantly reduced cytotoxicity in the liver compared with geldanymicin (Page and others, 1997). Currently 17AAG undergoes a phase 1/11 clinical studies.

Radicial, macrocyclic antibiotic, also causes a revision of the v-Src and v-Ha-Ras-Indus is one of the malignant phenotype of fibroblasts (Kwon and others, 1992; Zhao and others, 1995). Radical destroys a large number of signaling proteins in the inhibition of HSP90 (Schulte and others, 1998). Using crystallographic analysis with x-rays was shown that radical also binds to the N-terminal domain of HSP90 and inhibits internal ATP-asnow activity (Roe and others, 1998).

As you know, antibiotics coumarin-type contact ATP-binding site of HSP90 homolog DNA gyrase in bacteria. Coumarin, novobiocin, associated with carboxyterminal the end of HSP90, that is, to another site in the HSP90 than benzoquinone-ansamycin and radicial that are associated with the N-terminal end of HSP90 (Marcu and others, 2000b).

Inhibition of HSP90 by novobiocin leads to the collapse of a large number NR-dependent signaling proteins (Marcu and others, 2000a).

The collapse of signaling proteins such as ERBB2, shown with the use of PU3, an inhibitor of HSP90, which is a derivative of purine. PU3 causes cell cycle arrest and differentiation of cell lines breast cancer (Chiosis and others, 2001).

HSP90 as a therapeutic goals

Due to the involvement of HSP90 in the regulation of a large number of transmission signals, which are extremely important for the phenotype of the tumor, and the discovery that certain natural products exhibit their biological effects by inhibiting the activity of HSP90, HSP90 n is currently being investigated as a new target for development of anticancer therapeutic agent (Neckers and others, 1999).

The main mechanism of action geldanamycin, 17AAG and radicicola is the inhibition of the binding of ATP to the ATP-binding site in the N-terminal end of the protein and result in the inhibition of the internal ATP-aznoe activity of HSP90 (see, for example, Prodromou and others, 1997; Stebbins and others, 1997; Panaretou and others, 1998). Inhibition of ATP-aznoe activity of HSP90 prevents replenishment of co-chaperones and promotes the formation of HSP90 heterocomplex, which causes the breakdown of related proteins by the ubiquitin-proteasome mechanism (see, for example, Neckers and others, 1999; Kelland and others, 1999). Treatment of tumor cells with inhibitors of HSP90 leads to selective dissolution of important proteins with extreme importance in processes such as cell proliferation, regulation of cell cycle and apoptosis. This is often manifested by impaired regulation in tumors (see, for example, Hostein and others, 2001).

Favorable rationale for the development of the HSP90 inhibitor is the fact that it is possible to achieve effective antitumor action by the simultaneous disintegration of many proteins that are associated with the transformed phenotype.

In more detail, the present invention relates to compounds which inhibit, regulate and/or modulate HSP90, to compositions which contain these compounds, and to methods of their use for the ecene HSP90-induced diseases, such as tumor diseases, viral diseases, such as hepatitis b (Waxman, 2002); immunosuppression in transplant (Bijlmakers, 2000. and Yorgin, 2000); disease-induced inflammation (Bucci, 2000), such as revmatoidnij arthritis, asthma, multiple sclerosis, type I diabetes, lupus erythematosus, psoriasis and inflammatory bowel disease; cystic fibrosis (Fuller, 2000); diseases associated with angiogenesis (Hur, 2002, and Kurebayashi, 2001), such as, for example, diabetic retinopathy, hemangioma, endometriosis and tumor angiogenesis; infectious diseases; autoimmune diseases; ischemia; stimulation of nerve regeneration (Rosen and others, WO 02/09696; Degranco and others, WO 99/51223; Gold, US 6210974 Bl); fibrogenetic diseases, such as, for example, scleroderma, illness Wagner, systemic lupus, cirrhosis of the liver, keloid formation, interstitial nephritis and pulmonary fibrosis (Strehlow, WO 02/02123).

The invention also relates to the use of compounds in accordance with the invention for protection of normal cells against toxicity caused by chemotherapy, and for use in diseases, the main cause is improper installation or aggregation of proteins, such as, for example, prurigo, disease, Jakob-Creutzfeldt, Huntington's or Alzheimer's disease (Sittler, Hum. Mol. Genet., 10, 1307, 2001; Tratzelt and others, r.Nat. Acad. Sci., 92, 2944, 1995; Winklhofer, etc., J. Biol. Chem., 276, 4160, 2001). In the application WO 01/72779 described purine compounds and their use for the treatment GRP94 (homolog or paralogue S90)-induced diseases, such as neoplastic disease where malignant tissue includes a sarcoma or carcinoma, selected from the group including fibrosarcoma, malignant myxoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordomas, angiosarcoma, endothelioma, lymphangiosarcoma, lymphangiosarcoma, synovial endothelium, mesothelioma, Ewing sarcoma, LaserComb, rhabdomyosarcoma, a cancer of the colon, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell cancer, adenocarcinoma, cancer of the duct of the sweat gland, cancer of the cells of the sebaceous gland, papillary cancer, papillary adenocarcinoma, cystadenocarcinoma, cancer of the bone marrow, bronchogenic cancer, renal cell cancer, hepatic cell adenoma, bile duct cancer, horiokartsinoma, spermatozoa, embryonal carcinoma, Wilm tumor, cervical cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, the retinoblastoma, Le the goats, lymphoma, multiple myeloma, macroglobulinemia waldenstrom and heavy chain disease.

A.Kamal and others in Trends in Molecular Medicine, volume 10, No. 6, June 2004, described therapeutic and diagnostic applications activation of HSP90, in particular, for the treatment of diseases of the Central nervous system and cardiovascular diseases.

Therefore, it is desirable to identify small compounds which specifically inhibit, regulate and/or modulate HSP90, and it is an object of the present invention.

It was found that the compounds of formula I and their salts possess very valuable pharmacological properties, as well as good tolerability. In particular, they have any abscopal effect against HSP90.

Therefore, the present invention relates to compounds of the formula I as medicaments and/or active ingredients of medicines for the treatment and/or prevention of these diseases and to the use of compounds of formula I to obtain drugs for the treatment and/or prophylaxis of these diseases, as well as to method of treatment for these diseases, which includes the introduction of one or more compounds of formula I to a patient in need of such introduction.

The owner or the patient can be any mammal species, such as for example, the Primate, preferably human; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are of interest for experimental studies because they provide a model for the treatment of human diseases.

The level of technology

Other derivatives peridotite described as inhibitors of HSP90 in WO 2005/034950 and in WO 2005/021552.

In the application WO 2005/00300 A1 describes triazole derivatives as inhibitors of HSP90.

In the application WO 00/53169 described the inhibition of HSP90 by coumarin or a derivative of coumarin.

In the application WO 03/041643 A2 describes derivatives zearalanol that inhibit HSP90.

Derivatives of pyrazole, which inhibit HSP90, a substituted aromatic radical in 3rd or 5th position, described in the applications WO 2004/050087 A1 and WO 2004/056782 A1.

In the application WO 03/055860 A1 describes 3,4-diarylpyrazole as inhibitors of HSP90.

Derivatives of purine with any abscopal effect against HSP90, as described in the application WO 02/36075 A2.

In the application WO 01/72779 described purine compounds and their use for the treatment GRP94 (homolog or paralogue HSP90)-induced diseases, such as neoplastic disease where malignant tissue includes a sarcoma or carcinoma, selected from the group including fibrosarcoma, malignant myxoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordomas is, angiosarcoma, endothelioma, lymphangiosarcoma, lymphangiosarcoma, synovial endothelium, mesothelioma, Ewing sarcoma, LaserComb, rhabdomyosarcoma, a cancer of the colon, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, cancer of the duct of the sweat gland, cancer of the cells of the sebaceous gland, papillary cancer, papillary adenocarcinoma, cystadenocarcinoma, cancer of the bone marrow, bronchogenic cancer, renal cell cancer, hepatic cell adenoma, bile duct cancer, horiokartsinoma, spermatozoa, embryonal carcinoma, Wilm tumor, cervical cancer cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma, macroglobulinemia waldenstrom and heavy chain disease.

In addition, in WO 01/72779 described the use of these compounds for the treatment of viral diseases, where the viral pathogen is selected from the group including hepatitis type a, hepatitis type b, hepatitis type C, influenza, varicella, adenovirus, herpes simplex type I (HSV-I), the Rus herpes simplex type II (HSV-II), the plague of cattle, rhinovirus, Echovirus, rotavirus, respiratory syncytial virus (RSV), papillomavirus, papovavirus, cytomegalovirus, echinodorus, arbovirus, Hantavirus, Coxsackie virus, mumps virus, measles virus, rubella virus, polio virus, human immunodeficiency virus type I (HIV-I) and human immunodeficiency virus type II (HIV-II).

In addition, in WO 01/72779 described the use of these compounds for modulation of GRP94, where modulation of the biological activity of GRP94 cause an immune response in animals, transport of protein from the endoplasmic reticulum, recovery after hypoxic/anoxic stress, recovering from malnutrition, recovery from heat stress, or combinations thereof, and/or where the disease is a type of cancer, an infectious disease, a disorder associated with impaired transport of protein from the endoplasmic reticulum, a disorder associated with ischaemia/reperfusion or combinations thereof, where a disorder associated with ischaemia/reperfusion, is a consequence of the stop heart, asistoliei and delayed ventricular fibrillation, heart surgery, surgery, cardiopulmonary bypass surgery, organ transplant, spinal cord injury, head trauma, stroke, thromboembolic stroke, hemorragias the third blow, spasm of cerebral vessels, hypotension, hypoglycaemia, epileptic condition, seizures, anxiety, schizophrenia, a neurodegenerative disorder, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) or neonatal stress.

In conclusion, WO 01/72779 described the use of an effective amount of the protein modulator GRP94 for the preparation of medicines for changes subsequent cellular response to ischemic condition in the tissue specimens by processing cells in the tissue protein modulator GRP94 for such increase activity of GRP94 in the cells that have changed subsequent reaction of the cells to the ischemic state where subsequent ischemic condition preferably is a consequence of cardiac arrest, asistoliei and delayed ventricular fibrillation, heart surgery, surgery, cardiopulmonary bypass surgery, organ transplant, spinal cord injury, head trauma, stroke, thromboembolic stroke, hemorrhagic stroke, spasm of cerebral vessels, hypotension, hypoglycaemia, epileptic condition, seizures, anxiety, schizophrenia, a neurodegenerative disorder, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) or neonatal stress, or where the tissue submitted is a donor tissue for transplantation.

The invention

The invention relates to compounds of formula I

in which Y is HE, OA, SH, SA, NH2, NHA, NAA' or other5,

R1represents Hal, HE, OA, SH, SA, H or A,

R2, R3each, independently from each other represents-NHCO-(X)s-Q, -CONH-(X)s-Q, -CONA-(X)s-Q, -NH(CO)NH-(X)s-Q, -NH(CO)O-(X)s-Q, - NHSO2(X)s-Q, -SO2NH-(X)s-Q, -SO2NA-(X)s-Q, -(X)s-Q or H, where

if R2≠H, R3=H or Cl,

or if R3≠H, R2=H or Cl,

R4represents H, Hal, CN, NO2And, HE, OA, SH, SA, (CH2)nCOOH, (CH2)nCOOA, CONH2, CONHA, CONAA', NH2, NHA, NAA', NHCOOA, NHCONH2, NHCONHA, SOA, SO2A, SO2NH2, SO2NHA and/or SO2NAA',

two adjacent radicals selected from the group R1, R2, R3, R4,

together also represent methylenedioxy or Ethylenedioxy,

R5represents -(CH2)0-Het1, -(CH2)o-NH2, -(CH2)o-NHA or -(CH2)o-NA2,

A, a' each, independently of one another, represents an unbranched or branched alkyl containing 1-10 carbon atoms, in which 1-5 h atoms may be replaced by F, Cl and/or Br,

Alk or cyclic alkyl containing 3-7 at the MOU carbon A and a' together also represent alkylenes chain containing 2, 3, 4, 5 or 6 carbon atoms, in which one or two CH2-groups may be replaced by O, S, SO, SO2, NH, NA, and/or N-cooa,

Alk is alkenyl containing 2-6 carbon atoms,

X represents an unbranched or branched C1-C10alkylen or2-C10albaniles, each of which is unsubstituted or one-, two-, three - or tetraparesis A, OA, HE, SH, SA, Hal, NO2, CN, Ar, OAr, COOH, COOA, CHO, C(=O)A, C(=O)Ar, SO2A, CONH2, SO2NH2, CONHA, CONAA', SO2NHA, SO2NAA', NH2, NHA, NAA', OCONH2, OCONHA, OCONAA', NHCOA, NHCOOA, NACOOA, NHSO2OA, NASO2OA, NHCONH2, NACONH2, NHCONHA, NACONHA, NHCONAA', NACONAA' and/or =O and in which one, two or three groups may be replaced by O, S, SO, SO2, NHCO, NACO, CONH, CONA, SO2NH, SO2NA, NHSO2, NASO2and/or NH groups,

Q represents H, Carb, Ar or Het,

Carb is cycloalkyl containing 3-7 carbon atoms, or cycloalkenyl containing 3-7 carbon atoms, each of which is unsubstituted or mono-, bi-, tri-, Tetra - or pentosanase A, OA, HE, SH, SA, Hal, NO2CN, (CH2)nAr', (CH2)nCOOH, (CH2)nCOOA, CHO, COA, SO2A, CONH2, SO2NH2, CONHA, CONAA', SO2NHA, SO2NAA', NH2, NHA, NAA', OCONH2, OCONHA, OCONAA', NHCOA, NHCOOA, NACOOA, NHSO2OA, NASO2O, NHCONH2, NACONH2, NHCONHA, NACONHA, NHCONAA' and/or NACONAA',

Ar represents phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, bi-, tri-, Tetra - or pentosanase A, OA, HE, SH, SA, Hal, NO2CN, (CH2)nAr', (CH2)nCOOH, (CH2)nCOOA, Cho, COA, SO2A, CONH2, SO2NH2, CONHA, CONAA', SO2NHA, SO2NAA', NH2, NHA, NAA1, OCONH2, OCONHA, OCONAA', NHCOA, NHCOOA, NACOOA, NHSO2OA, NASO2OA, NHCONH2, NACONH2, NHCONHA, NACONHA, NHCONAA', NACONAA', NHCO(CH2)nNH2and/or-O-(CH2)o-Het1,

Ar' represents a phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, bi - or triamese A, OA, HE, SH, SA, Hal, NO2CN, (CH2)nthe phenyl, (CH2)nCOOH, (CH2)nCOOA, Cho, COA, SO2A, CONH2, SO2NH2, CONHA, CONAA', SO2NHA, SO2NAA', NH2, NHA, NAA', OCONH2, OCONHA, OCONAA', NHCOA, NHCOOA, NACOOA, NHSO2OA, NASO2OA, NHCONH2, NACONH2, NHCONHA, NACONHA, NHCONAA' and/or NACONAA',

Het is a mono - or bicyclic saturated, unsaturated or aromatic heterocycle containing from 1 to 4 atoms of N, O and/or S, which may be one-, two - or triamese A, OA, HE, SH, SA, Hal, NO2CN, (CH2)nAr', (CH2)nCOOH, (CH2)nCOOA, Cho, COA, SO2A, CONH2, SO2NH2, CONHA, CONAA', SO2NHA, SO2 NAA', NH2. NHA, NAA', OCONH2, OCONHA, OCONAA', NHCOA, NHCOOA, NACOOA, NHSO2OA, NASO2OA, NHCONH2, NACONH2, NHCONHA, NACONHA, NHCONAA', NACONAA', SO2A, =S, =NH, =NA and/or =O (carbonyl oxygen),

Het1represents a monocyclic saturated, a heterocycle containing 1 to 2 N atoms and/or which may be single - or dunamase A, OA, HE, Hal and/or =O (carbonyl oxygen),

Hal represents F, Cl, Br or I,

n represents 0, 1, 2, 3,or 4

o represents 1, 2, 3,or 4

s represents 0 or 1,

and their pharmaceutically usable derivative, salt, solvate, tautomers and stereoisomers, including mixtures thereof in all ratios.

The invention also relates to compounds of formula I and their salts and to a process for the preparation of compounds of formula I in accordance with paragraphs 1-14 and their pharmaceutically usable derivatives, solvate, salts, tautomers and stereoisomers, which is characterized by the fact that

a) compound of formula II

in which R1, R2and R3have the meanings specified in paragraph 1

subjected to reaction with the compound of the formula III

in which Y has the meaning specified in paragraph 1, and

Z represents Cl, Br, I or a free or reactive functionally modified HE-group

or

1, R2, R3, R4and/or Y in the compound of the formula I is converted into one or more radicals R1, R2, R3, R4and/or Y, for example, by

i) recovery of nitro group to amino group,

ii) hydrolysis of the ester group to a carboxyl group,

iii) the conversion of an amino group in alkilirovanny amine by reductive amination,

iv) alkylation and/or acylation of the hydroxyl and/or amino groups

and/or a base or acid of the formula I is converted into one of its salts.

The invention also relates to hydrate and solvate of these compounds. Under the solvate compounds mean adducts of molecules of the inert solvent for the compounds, which are formed due to their force of mutual attraction. The solvate represent, for example, mono - or dihydrate or alcoholate.

The compounds of formula I in accordance with the invention can also exist in tautomeric forms. Formula I encompasses all such tautomeric forms.

Under pharmaceutically usable derivatives implies, for example, salts of compounds in accordance with the invention, as well as the so-called prodrug compounds.

Derivatives of prodrugs include compounds of formula I, which are modified with alkyl or acyl groups, sugars or oligopo what Chida and are quickly broken down in the body with the formation of the active compounds in accordance with the invention.

It also includes derivatives of biodegradable polymers compounds in accordance with the invention, as described, for example, in Int. J. Pharm. 115, 61-67 (1995).

The expression "effective amount" means a quantity of a drug or pharmaceutical active component, which causes the biological or medical response that involves or is seeking to obtain, for example, a researcher or physician in a tissue, system, animal or human.

Additionally, the expression "therapeutically effective amount" refers to that amount which has the following consequences compared with a corresponding subject who has not received this amount:

improved treatment, healing, prevention or elimination of the disease, the picture of the disease, a painful condition, complaint, disorder or side effects or also the reduction of disease progression, complaints or disorders.

The expression "therapeutically effective amount" also encompasses amounts that are effective to enhance normal physiological functions.

The invention also relates to mixtures of compounds of formula I in accordance with the invention, for example mixtures of two diastereomers, for example in the ratio

1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000. Especially predpochtitel the YMI are a mixture of stereoisomeric compounds.

For all radicals which occur more than once, their meanings are independent of each other.

At the mention of above and below, the radicals or parameters R1, R2, R3, R4and Y have the meanings stated for formula I, unless expressly stated otherwise.

A or a' preferably represents alkyl which is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. A or a' preferably represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2 - or 3-methylbutyl, 1,1-, 1,2 - or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3 - or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3.3-dimethylbutyl, 1 - or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2 - or 1,2,2-trimethylpropyl. A or a' is most preferably represents alkyl containing 1, 2, 3, 4, 5 or 6 carbon atoms, preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1,1,1-triptorelin, in addition, also vermeil, deformity or methyl bromide.

A or a' is also cycloalkyl. Cycloalkyl preferably represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

A or a' is also Soboh the Alk. Alk is alkenyl containing 2-6 carbon atoms, such as, for example, vinyl or propenyl.

Cycloalkylation represents, for example, cyclohexylmethyl, cyclohexylethyl, cyclopentylmethyl or cyclopentylmethyl.

With1-C10alkylene preferably represents a methylene, ethylene, propylene, butylene, pentile, hexylen, reptile, octiles, Nonlin or decile, isopropylene, isobutylene, sec-butylene, 1-, 2 - or 3-methylbutyl, 1,1-, 1,2 - or 2,2-dimethylpropylene, 1-ethylpropyl, 1-, 2-, 3 - or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3.3-dimethylbutyl, 1 - or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2 - or 1,2,2-trimethylpropyl, more preferably methylene, ethylene, propylene, butylene, pentile or hexylen.

Albaniles represents a hydrocarbon chain containing 2 to 10 carbon atoms, with 2 two free valencies and containing at least one double bond.

AC represents acetyl, Bzl represents a benzyl, Ms represents-SO2CH3.

Y preferably represents amino; NHA preferably methylamino; NAA' preferably dimethylamino or diethylamino; other5preferably-NH-(CH2)o-NA2such as, for example, 2-diethylaminoethylamine, or-NH-(CH2)o-Het1such as, for example, 2-(Moholy the-4-yl)ethylamino.

Y preferably represents NH2.

R1preferably represents H, HE or OA, such as, for example, methoxy.

R2, R3preferably each, independently of one another, represents-NHCO-(X)s-Q, -CONH-(X)s-Q, -NH(CO)NH-(X)s-Q, -NH(CO)O-(X)s-Q, -(X)s-Q or N, where,

if R2≠N, R3=H or Cl, or

if R3≠H, R2=H or Cl.

R4preferably represents H or Hal, more preferably N.

X preferably represents an unbranched or branched C1-C10alkylene, which is unsubstituted or one-, two-, three - or tetraparesis OA, HE, Hal, COOH, CONH2, NH2and/or NHCOOA, and in which one, two or three groups may be replaced by O, NHCO, CONH, SO2NH, NHSO2and/or NH-groups.

Ar represents, for example, phenyl, o-, m - or p-tolyl, o-, m - or p-ethylphenyl, o-, m - or p-propylphenyl, o-, m - or p-isopropylphenyl, o-, m - or p-tert-butylphenyl, o-, m - or p-hydroxyphenyl, o-, m - or p-nitrophenyl, o-, m - or p-AMINOPHENYL, o-, m - or p-(N-methylamino)phenyl, o-, m - or p-(N-methylaminomethyl)phenyl, o-, m - or p-acetamidophenyl, o-, m - or p-methoxyphenyl, o-, m - or p-ethoxyphenyl, o-, m - or p-ethoxycarbonylphenyl, o-, m - or p-(N,N-dimethylamino)phenyl, o-, m - or p-(N,N-dimethylaminoethyl)phenyl, o-, m - or p-(N-ethylamino)phenyl, o-, m - is whether p-(N,N-diethylamino)phenyl, o-, m - or p-forfinal, o-, m - or p-bromophenyl, o-, m - or p-chlorophenyl, o-, m - or p-(methylsulfonylamino)phenyl, o-, m - or p-(methylsulphonyl)phenyl, o-, m - or p-cyanophenyl, o-, m - or p-braidotti, o-, m - or p-formylphenyl, o-, m - or p-acetylphenyl, -, m - or p-aminosulphonylphenyl, o-, m - or p-carboxyphenyl, o-, m-or p-carboxymethyl, o-, m - or p-carboxymethoxy, more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-differenl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4 - or 2,5-dinitrophenyl, 2,5 - or 3,4-acid, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro - or 2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino - 3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenol, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5 - trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, n-iopener, 3,6-dichloro-4-AMINOPHENYL, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2.5-debtor-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-were, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar preferably represents phenyl, which is unsubstituted or mono-, bi-, tri-, Tetra - or pentosanase A, Hal, OA, (CH2)nCOOH, (CH2)nCOOA, NHCO(CH2)nNH2and/or-O-(CH2)o-Het1.

Ar preferably represents phenyl, which is unsubstituted or mono - or dunamase A, Hal, (CH2)nCOOH, (CH2)nCOOA, NHCO(CH2)nNH2and/or-O-(CH2)o-Het1.

Ar' preferably represents, for example, phenyl, which is unsubstituted or mono-, bi - or triamese Hal.

Irrespective of further substitutions, Het represents, for example, 2 - or 3-furyl, 2 - or 3-thienyl, 1-, 2 - or 3-pyrrolyl, 1-, 2 -, 4-or 5-imidazolyl, 1-, 3-, 4 - or 5-pyrazolyl, 2-, 4 - or 5-oxazolyl, 3-, 4 - or 5-isoxazolyl, 2-, 4 - or 5-thiazolyl, 3-, 4 - or 5-isothiazole, 2-, 3 - or 4-pyridyl, 2-, 4-, 5 - or 6-pyrimidinyl, more preferably 1,2,3-triazole-1-, -4 - or-5-yl, 1,2,4-triazole-1-, -3 - or 5-yl, 1 - or 5-tetrazolyl, 1,2,3-oxadiazol-4 - or-5-yl, 1,2,4-oxadiazol-3 - or-5-yl, 1,3,4-thiadiazole-2 - or-5-yl, 1,2,4-the thiadiazole-3 - or-5-yl, 1,2,3-thiadiazole-4 - or-5-yl, 3 - or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6 - or 7-indolyl, 4 - or 5-isoindolyl, 1-, 2-, 4 - or 5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6 - or 7-indazole, 1-, 3-, 4-, 5-, 6 - or 7-benzimidazolyl, 2-, 4-, 5-, 6 - or 7-benzoxazolyl, 3-, 4-, 5-, 6 - or 7-benzisoxazole, 2-, 4-, 5-, 6 - or 7-benzothiazolyl, 2-, 4-, 5-, 6 - or 7-benzisothiazole, 4-, 5-, 6 - or 7-benzo-2,1,3-oxadiazole, 2-, 3-, 4-, 5-, 6-, 7 - or 8-chinolin, 1-, 3-, 4-, 5-, 6-, 7 - or 8-ethanolic, 3-, 4-, 5-, 6-, 7 - or 8-indolinyl, 2-, 4-, 5-, 6-, 7 - or 8-hintline, 5 - or 6-honokalani, 2-, 3-, 5-, 6-, 7 - or 8-2H-benzo-1,4-oxazinyl, more preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazole-4 - or-5-yl or 2,1,3-benzoxa eazol-5-yl.

Heterocyclic radicals can also be partially or fully gidrirovanny.

Het may also represent, for example, 2,3-dihydro-2-, -3-, -4 - or-5-furyl, 2,5-dihydro-2-, -3-, -4 - or 5-furyl, tetrahydro-2 - or-3-furyl, 1,3-dioxolane-4-yl, tetrahydro-2 - or-3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4 - or-5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4 - or-5-pyrrolyl, 1-, 2 - or 3-pyrrolidinyl, tetrahydro-1-, -2 - or-4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4 - or-5-pyrazolyl, tetrahydro-1-, -3 - or-4-pyrazolyl, 1,4-dihydro-1-, -2-, -3 - or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5 - or-6 - pyridyl, 1-, 2-, 3 - or 4-piperidinyl, 2-, 3 - or 4-morpholinyl, tetrahydro-2-, -3 - or-4-pyranyl, 1,4-dioxane, 1,3-dioxane-2-, -4 - or-5-yl, hexahydro-1-, -3 - or -4-pyridazinyl, hexahydro-1-, -2-, -4 - or-5-pyrimidinyl, 1-, 2 - or 3-piperazinil, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7 - or-8-chinolin, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7 - or -8-ethanolic, 2-, 3-, 5-, 6-, 7 - or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl, more preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-atlanticcity, 3,4-atlanticcity, 3,4-(diversitronics)phenyl, 2,3-dihydrobenzofuran-5 - or 6-yl, 2,3-(2-oxoethylidene)phenyl or also 3,4-dihydro-2H-1,5-benzodioxepin-6 - or-7-yl, more preferably 2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxoferryl.

Het preferably represents mono - or bicyclic saturated, unsaturated or arene the optical heterocycle, containing from 1 to 4 atoms of N, O and/or S, which may be one-, two - or triamese A, OA, Hal and/or =O (carbonyl oxygen).

Het preferably represents mono - or bicyclic saturated, unsaturated or aromatic heterocycle containing 1 to 2 N atoms and/or which may be single - or dunamase and/or =O (carbonyl oxygen), a preferably represents methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl or trifluoromethyl.

In a further embodiment of the invention more preferably Het is a piperidine, piperazine, pyrrolidine, pyridine, pyrrole, indole, indazole, morpholine or isoxazol, each of which is unsubstituted or mono - or dunamase and/or =O, where a preferably represents methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl or trifluoromethyl.

Het1preferably represents a monocyclic saturated, a heterocycle containing 1 to 2 N atoms and/or which may be single - or dunamase and/or =O (carbonyl oxygen), the most preferred is 4-methylpiperazine.

The compounds of formula I may have one or more chiral centers and therefore may occur in different stereoisomeric forms. Formula I encompasses all these forms.

Thus, the invention relates, in which lastnosti, the compounds of the formula I, in which at least one of these radicals has one of the preferred meanings indicated above. Some preferred groups of compounds can be represented by the following subformulas Ia-Im, which correspond to the formula I and in which the values of the radicals do not significantly differ from the values given for formula I, but in which

in Ia Y represents NH2or other5;

in Ib R1represents H, HE or OA;

in Ic R2, R3each, independently from each other represents-NHCO-(X)s-Q, -CONH-(X)s-Q, -NH(CO)NH-(X)s-Q, -NH(CO)O-(X)s-Q, -(X)s-Q or N,

where, if R2≠N, R3=H or Cl, or

if R3≠N, R2=H or Cl;

in Id R4represents H or Hal;

in Ie R5represents -(CH2)o-Het1or -(CH2)o-NA2;

If X represents an unbranched or branched C1-C10alkylene, which is unsubstituted or one-, two-, three - or tetraparesis OA, HE, Hal, COOH, CONH2, NH2and/or NHCOOA, and in which one, two or three groups may be replaced by O, NHCO, CONH, SO2NH, NHSO2and/or NH groups;

in Ig Q represents H, Ar or Het;

in Ih Ar represents phenyl, which is unsubstituted or mono-, bi-, tri-, Tetra - or pentosanase A, Hal, OA, (CH2 )nCOOH, (CH2)nCOOA, NHCO(CH2)nNH2and/or-O-(CH2)about-Het1;

in Ii Het is a mono - or bicyclic saturated, unsaturated or aromatic heterocycle containing from 1 to 4 atoms of N, O and/or S, which may be one-, two - or triamese A, OA, Hal and/or =O (carbonyl oxygen);

in Ij Het is a mono - or bicyclic saturated, unsaturated or aromatic heterocycle containing 1 to 2 N atoms and/or which may be single - or dunamase and/or =O (carbonyl oxygen);

in Ik Het1represents a monocyclic saturated, a heterocycle containing 1 to 2 N atoms and/or which may be single - or dunamase and/or =O (carbonyl oxygen);

in Il And represents an unbranched or branched alkyl containing 1-6 carbon atoms, in which 1-5 h atoms may be replaced by F and/or Cl;

in Im Y represents NH2or other5,

R1represents H, HE or OA,

R2, R3each, independently from each other represents-NHCO-(X)s-Q, -CONH-(X)s-Q, -NH(CO)NH-(X)s-Q, -NH(CO)O-(X)s-Q, -(X)s-Q or N,

where, if R2≠N, R3=H or Cl, or

if R3≠N, R2=H or Cl;

R4represents H or Hal,

R5represents -(CH2 )o-Het1or -(CH2)o-NA2;

X represents an unbranched or branched C1-C10alkylene, which is unsubstituted or one-, two-, three - or tetraparesis OA, HE, Hal, COOH, CONH2, NH2and/or NHCOOA, and in which one, two or three groups may be replaced by O, NHCO, CONH, SO2NH, NHSO2and/or NH-groups

Q represents H, Ar or Het,

Ar represents phenyl, which is unsubstituted or mono-, bi-, tri-, Tetra - or pentosanase A, Hal, OA, (CH2)nCOOH, (CH2)nCOOA, NHCO(CH2)nNH2and/or-O-(CH2)o-Het1,

Het is a mono - or bicyclic saturated, unsaturated or aromatic heterocycle containing from 1 to 4 atoms of N, O and/or S, which may be one-, two - or triamese A, OA, Hal and/or =O (carbonyl oxygen),

Het1represents a monocyclic saturated, a heterocycle containing 1 to 2 N atoms and/or which may be single - or dunamase and/or =O (carbonyl oxygen),

And represents an unbranched or branched alkyl containing 1-6 carbon atoms, in which 1-5 h atoms may be replaced by F and/or Cl,

Hal represents F, Cl, Br or I,

n represents 0, 1, 2, 3,or 4

o represents 1, 2, 3,or 4

s represents 0 or 1;

and farmatsevticheskiye derivatives, the solvate, salts, tautomers and stereoisomers, including mixtures thereof in all ratios.

The compounds of formula I are preferably selected from group "A35", "A36", "A37 and A38".

Compounds in accordance with the invention, as well as source materials for their production can also be obtained by methods known per se, as described in the literature (for example in standard works such as Houben-Weyl, Methods der organischen Chemie [Methods of organic chemistry], Georg-Thieme-Verlag, Stuttgart), under reaction conditions which are known and acceptable for these reactions. Also you can apply various modifications, which are known per se but which is not mentioned in detail here.

If necessary, the original substances can also be formed in situ such that they do not stand out from the reaction mixture, but then they are directly converted to compounds in accordance with the invention.

The parent compound, as a rule, are known. However, if they are new, they can be obtained by methods known per se.

The compounds of formula I can preferably be obtained by reacting the compounds of formula II with the compound of the formula III. Compounds of formulas II and III, as a rule, are known. However, if they are new, they can be obtained by the methods, izvestnymi se.

In compounds of formula III Z preferably represents Cl, Br, I or a reactive modified IT group, such as alkylsulfonate containing 1-6 carbon atoms (preferably, methylsulfonylamino) or arylsulfonate containing 6-10 carbon atoms (preferably phenyl - or p-tolilsulfonil). Z preferably represents Cl.

The reaction is carried out using methods known to the person skilled in the technical field.

The reaction is preferably carried out under alkaline conditions. Suitable bases are preferably hydroxides of alkali metals including potassium hydroxide, sodium hydroxide and lithium hydroxide; hydroxides of alkaline earth metals such as barium hydroxide and calcium hydroxide; alkoxides of alkali metals, such as ethanolate potassium and propanol sodium, and various organic bases, such as pyridine or diethanolamine.

Usually the reaction is carried out in a suitable inert solvent.

Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or Tr is t-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as etilenglikolevye or monotropy ether or etilenglikolevye ether (diglyme); ketones, such as acetone or butanone; amides, such as ndimethylacetamide, dimethylacetamide or dimethylformamide (DMF); NITRILES, such as acetonitrile; sulfoxidov, such as dimethylsulfoxide (DMSO); carbon disulfide, carboxylic acids such as formic acid or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures these solvents.

The solvent preferably is, for example, water and/or tetrahydrofuran.

Depending on the applied conditions, the duration of reaction is in the range from several minutes to 14 days, and the reaction temperature is in the range from about -30 to 140°C, usually in the range from -10 to 130°C, in particular from about 30 to about 125°C.

In addition, it is possible to convert the compound of formula I into another compound of formula I by turning one or more radicals R1, R2, R3, R4and/or Y in one or more radicals R', R2, R3, R4and/or Y, for example by reducing nitro groups to amine the groups, for example by hydrogenation on Raney Nickel or Pd/coal in an inert solvent, such as methanol or ethanol, and/or

conversion of the ester group into a carboxyl group and/or conversion of the amino group in alkilirovanny amine by reductive amination and/or

esterification of carboxyl groups by reacting with alcohols and/or conversion of acid chlorides of the acids in acid amide by reaction with an amine and/or

alkylation of the hydroxyl group, for example, using alkylhalogenide.

Furthermore, free amino groups can be etilirovany appropriately using the acid chloride or acid anhydride or alkylated using an unsubstituted or substituted alkylhalogenide favorably in an inert solvent such as dichloromethane or THF, and/or in the presence of a base such as triethylamine or pyridine, at a temperature in the range from -60 to +30°C.

The compounds of formula I can also be obtained by selection in a free state of their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis.

The preferred initial agents for the solvolysis or hydrogenolysis are those which contain corresponding protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl the x groups, preferably those that carry the amino-protective group instead of a hydrogen atom bound to the nitrogen atom, for example those which correspond to formula I, but carry other' group (in which R' represents an amino-protective group, for example BOC or CBZ) instead of NH2group.

In addition, preferred are the starting substances, which are hydroxyl-protective group instead of a hydrogen atom of the hydroxyl group, for example those which correspond to formula I, but contain R"O-phenyl group (in which R represents a hydroxyl-protective group) instead hydroxyproline group.

There is also the possibility of the presence in the molecule of the original substance of many - same or different - protected amino and/or hydroxyl groups. If present protective groups differ from each other, in many cases, they can be selectively split.

The term "amino protective group" generally known and relates to groups which are suitable for protecting (blocking) an amino group from chemical reactions but which can be easily removed after the desired chemical reaction has been carried out in another part of the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl group, aryl group, arelaxation group or kalkilya g is the SCP. Since the amino protective groups are removed after the desired reaction (or sequence of reactions), their type and size are also critical; however, preference is given to those which have 1-20, in particular 1-8, carbon atoms. The term "acyl group" should be understood in its broadest sense, in connection with the present method. It includes acyl groups derived from aliphatic, alifaticheskih, aromatic or heterocyclic carboxylic acids or sulfonic acids and, in particular, alkoxycarbonyl, aryloxyalkyl and especially alcoxycarbenium group. Examples of such acyl groups are alkanoyl, such as acetyl, propionyl, butyryl; arkanoid, such as phenylacetyl; aroyl, such as benzoyl and tolyl; aryloxyalkanoic, such as POA; alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, 2,2,2-trichlorocyanuric, VOS and 2-iodoxybenzoic; arelaxation, such as CBZ ("carbobenzoxy"), 4-methoxybenzeneboronic and FMOC; arylsulfonyl, such as Mtr, Pbf or Pmc.

Preferred amino protective groups are BOC and Mtr, in addition, CBZ, Fmoc, benzyl and acetyl.

The term "hydroxyl protective group" is generally known and relates to groups which are suitable for protecting a hydroxyl group from chemical reactions but which easily beats the are after as the desired chemical reaction has been carried out in another part of the molecule. Typical of such groups are the abovementioned unsubstituted or substituted aryl, kalkilya or acyl group, in addition, also alkyl groups. The nature and size of the hydroxyl protective groups are not critical as they are removed after the desired chemical reaction or sequence of reactions; preference is given to groups that have 1-20, in particular 1-10, carbon atoms. Examples of hydroxyl protective groups are, among others, benzyl, n-nitrobenzoyl, p-toluensulfonyl, tert-butyl and acetyl, where benzyl and tert-butyl are particularly preferred. The COOH group is preferably protected as tert-butyl esters.

The compounds of formula I is isolated in a free state of their functional derivatives - depending on the protective group, for example using strong acids, mainly using TFU or perchloro acid, but also using other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, or sulfonic acids such as benzene - or p-toluensulfonate acid. The presence of an additional inert solvent Pets, but not always necessary is. Acceptable inert solvents are preferably organic, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such as DMF, halogenated hydrocarbons such as dichloromethane, in addition, also alcohols, such as methanol, ethanol or isopropanol, and water. Also acceptable is a mixture of the above solvents. TFU is preferably used in excess without the addition of another solvent, and perchloro acid preferably used in the form of a mixture of acetic acid and 70% perchloro acid in the ratio 9:1. The temperature of the reaction to effect the cleavage is preferably in the range between approximately 0 and approximately 50°C, preferably between 15 and 30°C (room temperature).

The BOC, OBut, Pbf, Pmc and Mtr groups can, for example, preferably to be derived using TFU in dichloromethane or using approximately 3-5 N. HCl in dioxane at 15-30°C, and the FMOC group can be derived using approximately 5-50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°C.

Pharmaceutical salts and other forms

Compounds disclosed in the invention can be used in their final mesolevel form. On the other hand, the present invention also relates to the application of the Oia such compounds in the form of their pharmaceutically acceptable salts, which can be obtained using a variety of organic and inorganic acids and bases in accordance with methods well known in the art. Pharmaceutically acceptable forms of the salts of the compounds of formula I are prepared mainly using traditional methods. If the compound of formula I contains a carboxylic acid group, it is acceptable salt can be formed through reaction of the compounds with acceptable base to obtain the corresponding salt of attaching the base. Examples of such bases are the hydroxides of alkali metals including potassium hydroxide, sodium hydroxide and lithium hydroxide; hydroxides of alkaline earth metals such as barium hydroxide and calcium hydroxide; alkoxides of alkali metals, such as ethanolate potassium and propanol sodium, and various organic bases, such as piperidine, diethanolamine and N-methylglucamine. Also included are aluminum salts of compounds of formula I. For some compounds of formula I salt accession acid can be formed by processing the indicated compounds with pharmaceutically acceptable organic and inorganic acids, such as hydrohloride, such as the hydrochloride, hydrobromide or hydroiodide; other mineral acids and their sootvetstvuyushiye, such as sulfate, nitrate or phosphate, and others; and alkyl - and monoacrylate, such as aconsultant, toluensulfonate and bansilalpet; and other organic acids and their corresponding salts such as acetate, triptorelin, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate, etc. Thus, pharmaceutically acceptable salt accession acid compounds of formula I include salts, but not limited to: acetate, adipate, alginate, arginate, aspartate, benzoate, bansilalpet (besylate), bisulfate, bisulfite, bromide, butyrate, comfort, camphorsulfonate, kaprilat, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrophosphate, dinitrobenzoate, dodecyl sulphate, aconsultant, fumarate, galactarate (from the mucus acid), galacturonic, glucoheptonate, gluconate, glutamate, glycerol, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonic, iodide, isothionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydratefast, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate.

In addition, ò salt compounds in accordance with what Britanie include, but not limited to, aluminum salts, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium, sodium and zinc. Preferred among the above salts are ammonium; alkali metal salts of sodium and potassium, and salts of alkaline earth metals calcium and magnesium. Salts of compounds of formula I which are derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines, also including natural substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenziletilendiaminom (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, Ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, geranamine, Isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, Tripropylamine and Tris(hydroxymethyl)methylamine (tromethamine).

Compounds in accordance with the present invention, which include basic nitrogen-containing groups can be stereoselectivity using takihiro, as With1-C4-alkylhalogenide, for example methyl-, ethyl-, isopropyl-tert-butylchloride, bromides and iodides; di-C1-C4the alkyl sulphates, for example dimethyl-, diethyl - and dimycolate; C10-C18-alkylhalogenide, for example decyl-, dodecyl-, lauryl-, myristyl and sterilgarda, bromides and iodides; and aryl-C1-C4-alkylhalogenide, for example, benzylchloride and geneticbased.

These salts help to get as soluble in water and soluble oil compounds in accordance with the invention.

Preferred pharmaceutical salts mentioned above, include, but are not limited to, acetate, triptorelin, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isothionate, mandelate, meglumin, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine.

An acid additive salt ò compounds of formula I are obtained by bringing into contact of the form of the free bases with a sufficient amount of the desired acid to produce the salt in the traditional way. The free base can be regenerated by bringing into contact of the salt form with a base and allocate the free base in the traditional way. The form of the free base to some extent differ from those with whom both relevant forms salts with their specific physical properties, such as solubility in polar solvents, but in the rest of the salts are equivalent to their respective shapes of the free bases for the purposes of the present invention.

As mentioned, pharmaceutically acceptable salts joining the Foundation of the compounds of formula I are formed with metals or amines, such as alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. The preferred organic amines are N,N'-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, Ethylenediamine, N-methyl-D-glucamine and procaine.

Salt joining the Foundation of acidic compounds in accordance with the invention is obtained by bringing into contact of the form of the free acid with a sufficient amount of the desired base to obtain the salt in the traditional way. The form of the free acid can be regenerated by bringing it in contact form salts with acid and the selection of the form of the free acid in a known manner. The form of the free acid to some extent differ from their corresponding forms of salts of certain physical properties, such as solubility in polar solvents, but in the rest of the salts are equivalent to their respective forms of St. the free acid for purposes of the present invention.

If the connection is in accordance with the invention includes more than one group, which are capable of forming pharmaceutically acceptable salts of this type, the invention also encompasses a compound of salt. Examples of typical composite forms salts include, but are not limited to, bitartrate, diacetate, difumarat dimeglumine, diphosphate, disodium and trihydrochloride.

In light of the above, you can see that the expression "pharmaceutically acceptable salt" in the context of this application is intended to indicate an active component that includes a compound of formula I in the form of their salts, in particular if this salt form provides the specified active ingredient improved pharmacokinetic properties as compared with the free form of said active ingredient or another salt of the indicated active ingredient, which was used previously. Pharmaceutically acceptable salt form of the active component may also initially to provide the desired pharmacokinetic property of the specified active component, which he did not previously possess, and may even positively affect the pharmacodynamics of the specified active ingredient with respect to its therapeutic activity in the body.

The compounds of formula I in accordance with the invention can be chiral is due to their molecular structure and therefore may occur in different enantiomeric forms. They can therefore exist in racemic or in optically active form.

As the pharmaceutical activity of racemates or stereoisomers of the compounds of formula I may be different, it may be desirable to use enantiomers. In these cases, the final product or even intermediate products can be separated into enantiomeric compounds of chemical or physical methods known to the person skilled in the field of technology, or even be used as such in the synthesis.

In the case of racemic amines diastereoisomers separated from the mixture by reaction with optically active separating agent. Examples of suitable separating agents are optically active acids, such as R - and S - forms of tartaric acid, diatsetilvinny acid, dibenzoyltartaric acid, almond acid, malic acid, lactic acid, suitable N-protected amino acids (for example, N-benzoylpyridine or N-benzosulfonazole), or the various optically active camphorsulfonic acid. Also preferred is the chromatographic separation of enantiomers using optically active separating agent (for example, dinitrobenzophenone, cellulose triacetate or other derivatives of hydrocarbons or chiral modified methacrylate polymers, immobilized on Sealy is agile). Suitable for this purpose suenami are aqueous or alcoholic solvent mixtures, such as, for example, hexane/isopropanol/acetonitrile, for example, in the ratio of 82:15:3.

The invention also relates to the use of compounds and/or their physiologically acceptable salts for the preparation of the medicinal product (pharmaceutical composition), in particular, using non-chemical methods. They can be converted into a suitable dosage form together with at least one solid, liquid and/or semi-liquid excipient or auxiliary substance and, if necessary, in combination with one or more other active ingredients.

The invention also applies to medicines containing at least one compound of the formula I and/or pharmaceutically usable derivative, solvate and stereoisomers, including mixtures thereof in all ratios, and optionally excipients and/or auxiliary substances.

The drugs can be administered in the form of dosage units that contain a predetermined quantity of active ingredient in dosage unit. Such a unit may include, for example, from 0.1 mg to 3 g, preferably 1 mg to 700 mg, more preferably from 5 mg to 100 mg, of the compounds according to the invention depending on bresnen the condition being treated, the method of administration and the age, weight and condition of the patient, or pharmaceutical compositions can be administered in the form of dosage units that contain a predetermined quantity of active ingredient in dosage unit. Preferred dosage units of drugs are those containing a daily dose or a part of the daily doses, as described above, or an appropriate portion of their active component. Drugs of this type can also be obtained by the method, which is well known in the pharmaceutical field.

Drugs may be adapted for administration by any suitable method, for example by the oral (including buccal or sublingual), rectal, nasal, local (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) administration. Such preparations can be prepared using any method known in the pharmaceutical field, for example, by combining the active ingredient with the excipient(s) or minor(s) substance(s).

Drugs, adapted for oral administration may be in the form of separate units such as, for example, capsules or tablet and; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam food; liquid emulsions oil-in-water or liquid emulsions water-in-oil.

For example, in the case of oral administration in the form of tablets or capsules, the active ingredient may be combined with an oral, non-toxic and pharmaceutically acceptable inert fillers, such as, for example, ethanol, glycerin, water, etc. Powders obtained by grinding connection to a suitable small size and mixing it with the pharmaceutical filler, crushed in a similar way, such as, for example, food hydrocarbon, such as, for example, starch or mannitol. You can also add flavoring, preservative, dispersing agent and a dye.

Capsules are produced by preparing a powder mixture as described above, and fill her gelatine capsules in a certain form. Before filling the capsules to the powder mixture, you can add sliding and lubricating agents such as, for example, highly dispersed silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form. To improve the availability of the medicinal product contained in the capsule, you can also add dezintegriruetsja substance or a solubilizer, such as, for example, agar-Aga is, calcium carbonate or sodium carbonate.

Additionally, if it is desirable or necessary, the mixture can also be added suitable binders, lubricants, disintegrators, and dyes. Suitable binders include starch, gelatin, natural sugars, such as glucose or beta-lactose, sweeteners made from corn, natural and synthetic rubber, such as, for example, Arabian gum, tragacanth gum or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and other lubricants that can be used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrators include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum and other Medicines in pill form get, for example, by preparing a powder mixture, granulating or dry pressing of a mix, adding lubricants and disintegrator and pressing the mixture into tablets. A powder mixture is prepared by mixing compound, comminuted in a suitable manner, with a diluent or base as described above, and optionally with a binder, such as, for example, carboxymethylcellulose, al is ginat, gelatine or polyvinylpyrrolidone, a dissolution retarder, such as, for example, paraffin, an amplifier, absorption, such as, for example, a Quaternary salt, and/or absorbent material, such as, for example, bentonite, kaolin or dicalcium phosphate. The powder mixture can be pelletized by wetting with a binder such as syrup, starch paste, mucilage of acacia or solutions of cellulose or polymeric substances, and pressing it through a sieve. Alternatively, the granulation of the powder mixture can pass through tablet press machine, receiving pieces of irregular shape, which disintegrate, forming granules. The pellets can be zamalevat by adding stearic acid, stearate, talc or mineral oil to prevent adhesion in tablet press mold. Then smeared the mixture is pressed, receiving tablets. Compounds in accordance with the invention can also be combined with bulk inert filler and then subjected to direct pressing, getting pills without implementation stages of granulation or dry pressing. Tablets also can be coated transparent or opaque protective layer consisting of shellac sealing layer, a layer of sugar or polymeric substances and glossy layer of wax. These coatings can also be added dyes available for the STI distinguish between different dosing units.

Liquids for oral administration, such as solution, syrups and elixirs can be prepared in the form of dosage units so that they contain a predetermined number of connections. Syrups can be obtained by dissolving the compound in an aqueous solution with a suitable flavoring, while elixirs are prepared using non-toxic alcohol filler. Suspensions can be prepared by dispersing the compound in a non-toxic filler. You can also add soljubilizatory and amplificatory, such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene esters of sorbitol, preservatives, flavoring agents, such as, for example, peppermint oil, or natural sweeteners or saccharin or other artificial sweeteners, etc.

The medicinal preparations for oral administration in the form of dosage units can be encapsulated in microcapsules, if this is desirable. Also the drug can be prepared in such a way as to prolong or slow release, for example, by applying a coating or sealing of the desired substance in polymers, wax, etc.

The compounds of formula I and their salts, solvate and physiologically functional derivatives can also enter the change in the form of liposomal delivery systems, such as, for example, a small single-layer vesicles, large single bubbles and multi-layered vesicles. Liposomes can be formed using a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.

The compounds of formula I and their salts, solvate and physiologically functional derivatives can also be delivered using monoclonal antibodies as individual carriers to which the attached molecule compounds. The connection can also be connected with soluble polymers as a target of drug delivery vehicles. Such polymers can include polyvinylpyrrolidone, a copolymer of Piran, polyhydroxyethylmethacrylate, polyhydroxyethylmethacrylate or polyethylene oxide of polylysine, substituted palmitoleate radicals. In addition, the compounds can be associated with a biodegradable polymer, which is suitable for controlled release of a drug, for example polylactic acid, poly-Epsilon-caprolactone, polyhydroxyalkanoic acid, polyarteritis, polyacetylene, policyidreference, polycyanoacrylates and cross-stitched or amphipatic block copolymers of hydrogels,

Drugs, adapted for transdermal administration, mohummmadiyya as independent patches for elongated, close contact with the epidermis of the recipient. Thus, for example, the active ingredient may be delivered from the patch by iontophoresis, as described in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compositions adapted for topical administration, can be prepared in the form of ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, spreeuw, aerosols or oils.

For treatment of the eye or other external tissues, for example mouth and skin, preferably used drugs in the form of local ointments or creams. For the preparation of a medicinal product in the form of an ointment, the active ingredient can be used with paraffin or miscible with water ointment base. Alternative to get cream the active ingredient can be prepared with a base for cream of type oil-in-water or the basis of the water-in-oil.

Drugs, adapted for local injection into the eye include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, preferably in an aqueous solvent.

Drugs, adapted for the local introduction into the oral cavity include cakes, lozenges and liquid rinse mouth.

Drugs, adapted for rectal administration, can be in the form of suppositories, or to the var.

Drugs, adapted for intranasal route, in which the carrier is a solid include a large powder having a particle size, for example, in the range of 20-500 microns, which is administered by inhalation, i.e. by rapid inhalation through the nose of the container containing the powder, which is held near the nose. Suitable drugs for administration in the form of intranasal spray or nasal drops of a liquid as a carrier include solutions of the active substance in water or in oil.

Drugs, adapted for administration by inhalation include fine particles in the form of dust or mist, which can be obtained using various dispersing device under pressure with aerosols, nebulizers or insufflators.

Drugs, adapted for vaginal administration, can be in the form of pessaries, tampons, creams, gels, pastes, foams or sprays.

Drugs, adapted for parenteral administration include aqueous or non-aqueous sterile injection solutions, which contain antioxidants, buffers, bacteriostatic substances and dissolved substances through which the drug is supported isotonic with respect to blood recipient is a, being treated, and aqueous or non-aqueous sterile suspensions, which may contain a suspension medium and thickeners. Medications can be entered using containers for single or multiple injections, for example sealed ampoules and vials, and stored in a dried state, while just before the introduction only need to add the sterile liquid carrier, for example water for injection.

Solutions and suspensions for injection, prepared according to the recipe can be prepared from sterile powders, granules and tablets.

Also it is obvious that in addition to the above-described preferred components, medicines can also contain other substances that are used in this area for specific types of drugs; for example, pharmaceutical preparations suitable for oral administration may include flavoring agents.

A therapeutically effective amount of the compounds of formula I depends on many factors, including, for example, the age and weight of a person or animal a particular state, should be treated, and its severity, the nature of the medicinal product and route of administration, and ultimately, it can be determined by the attending physician or veterinarian. However, effective to the number of connections in accordance with the invention, as a rule, is in the range from 0.1 to 100 mg/kg body weight of recipient (mammal) per day and preferably is typically in the range from 1 to 10 mg/kg of body weight per day. Therefore, the effective daily amount for an adult mammal weighing 70 kg can typically range from 70 to 700 mg, and this number can be entered as a single dose once daily or usually in the form of cycles of partial doses (such as, for example, two, three, four, five or six times a day, so that the total daily dose is similar. An effective amount of salt or MES or physiologically functional derivative can be defined as a proportion of the effective amount of the compounds according to the invention per se. It is also assumed that this dose is suitable for the treatment of other conditions specified in this application.

In addition, the invention relates to medicines that contain at least one compound of the formula I and/or pharmaceutically usable derivative, solvate and stereoisomers, including mixtures thereof in all ratios, and at least one additional active component of the medicinal product.

Additional active components of drugs preferably are chemotherapeutic agents, in particular the spine of those which inhibit angiogenesis and, consequently, inhibit the growth and proliferation of tumor cells; preferred according to the present invention are inhibitors of VEGF receptor, including roboski and antisense molecules which are directed to the receptors of VEGF, angiostatin and endostatin

Examples of anti-cancer tools that can be used in combination with the compounds according to the present invention, are typically alkylating tools, antimetabolites; epidophyllotoxin; anticancer enzyme, inhibitor topoisomerase; procarbazine; mitoxantrone or coordination complexes of platinum.

Anticancer means preferably selected from the following classes: anthracyclines, medicines periwinkle, mitomycin, bleomycin, the cytotoxic nucleosides, epothilone, discommodity, pteridine, deeney and podophyllotoxin.

More preferred in these classes are, for example, karminomitsin, daunorubicin, aminopterin, methotrexate, methopterin, dichloromethotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 5-ftordezoksiuridin monophosphate, cytarabine, 5-azacytidine, tioguanin, azathioprine, adenosine, pentostatin, erythrohydrobupropion, cladribine, 6-mercaptopurine, gemcitabine, cytarabine, podophyllotoxin or derivatives podofillotoksina, such as, for example etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vinorelbine, vincristine, leirosidin, vindesine, Larsen, docetaxel and paclitaxel. Other preferred anti-cancer tool is chosen from the group comprising diarmaid, epothilone D, estramustin, carboplatin, cisplatin, oxaliplatin, cyclophosphamide, bleomycin, gemcitabine, ifosfamide, melphalan, hexamethylmelamine, thiotepa, edatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, arabinosylcytosine, bikalutamid, flutamide, leuprolide, derivatives pyridobenzoxazine, interferons and interleukins.

Additional active components of drugs preferably are antibiotics. Preferred antibiotics are selected from the group including dactinomycin, daunorubicin, idarubitsin, epirubicin, mitoxantrone, bleomycin, plicamycin, mitomycin.

Additional active components of drugs preferably are enzyme inhibitors. Preferred inhibitors of the enzymes selected from the group including inhibitors of histone deacetylases (for example, suberoylanilide hydroxamic acid [SAHA]) and tyrosine kinase inhibitors (for example, ZD 1839 [Iressa]).

Additional active components of drugs preferably are inhibitors of nuclear export. Inhibitors poison is REGO export prevents the release of biopolymers (e.g., RNA from the cell nucleus. Preferred inhibitors of nuclear export selected from the group including callistemon, leptomycin, ratsadon.

Additional active components of drugs preferably are inhibitors of nuclear export. Inhibitors of nuclear export prevents the release of biopolymers (e.g., RNA from the cell nucleus. Preferred inhibitors of nuclear export selected from the group including callistemon, leptomycin, ratsadon.

Additional active components of drugs preferably are immunosuppressants. Preferred immunosuppressive agents selected from the group comprising rapamycin, CCI-779 (Wyeth), RAD001 (Novartis), AP23573 (Ariad Pharmaceuticals).

The invention also relates to a set (kit)consisting of separate packs

(a) an effective amount of the compounds of formula I and/or pharmaceutically usable derivatives, solvate and stereoisomers, including mixtures thereof in all ratios, and

(b) an effective amount of an additional active component of the medicinal product.

Kit includes suitable containers, such as cartons, individual bottles, packages or capsules. The kit may include, for example, separate ampoules each containing an effective amount of the compounds of formula I and/or Pharma is efticiency suitable derivatives, the solvate and stereoisomers, including mixtures thereof in all ratios, and an effective amount of an additional active component of the drug in dissolved or liofilizirovannoe form.

Application

Compounds according to the present invention is suitable as a pharmaceutically active ingredients for mammals, especially for humans, for the treatment of diseases involving HSP90.

Consequently, the invention relates to the use of compounds of the formula I and their pharmaceutically usable derivative, solvate and stereoisomers, including mixtures thereof in all ratios, for the preparation of drugs for the treatment of diseases that are affected by the inhibition, regulation and/or modulation of HSP90.

It is preferable to use compounds of the formula I and their pharmaceutically usable derivative, solvate and stereoisomers, including mixtures thereof in all ratios, for the preparation of drugs for the treatment of neoplastic diseases, such as fibrosarcoma, malignant Mikami, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, ehotelier.com, lymphangiosarcoma, lymphangiosarcoma, synovial endothelium, mesothelioma, Ewing sarcoma, lasercom, rhabdomyosarcoma, colon cancer, pancreatic cancer W is Lesa breast cancer, ovarian cancer, prostate cancer, squamous cell cancer, basal cell carcinoma, adenocarcinoma, cancer of the duct of the sweat gland, cancer of the cells of the sebaceous gland, papillary cancer, papillary adenocarcinomas, cystadenocarcinoma, of bone marrow cancer, bronchogenic cancer, renal cell cancer, hepatic cell adenoma, bile duct cancer, choriocarcinoma, spermatocyte, embryonal carcinoma, Wilm tumor, cervical cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, gliomas, astrocytomas, Protocol, craniopharyngioma, ependymomas pinealoma, hemangioblastoma, neurinomas of the auditory nerve, oligodendrogliomas, meningiomas, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma, macroglobulinemia waldenstrom and heavy chain disease; viral diseases, where the viral pathogen is selected from the group including hepatitis type a, hepatitis type b, hepatitis type C, influenza, varicella, adenovirus, herpes simplex type I (HSV-I), herpes simplex type II (HSV-II), the plague of cattle, rhinovirus, Echovirus, rotavirus, respiratory syncytial virus (RSV), papillomavirus, papovavirus, cytomegalovirus, echinodorus, arbovirus, Hantavirus, Coxsackie virus, mumps virus, measles virus, virusrescue, the polio virus, human immunodeficiency virus type I (HIV-I) and human immunodeficiency virus type II (HIV-II); for immunosuppression in transplant; diseases induced by inflammation, such as revmatoidnij arthritis, asthma, multiple sclerosis, type I diabetes, lupus erythematosus, psoriasis and inflammatory bowel disease; cystic degeneration, diseases associated with angiogenesis, such as, for example, diabetic retinopathy, hemangioma, endometriosis, tumor angiogenesis; infectious diseases; autoimmune diseases; ischemia; stimulation of nerve regeneration; fibrogenetic diseases such as, for example, scleroderma, illness Wagner, systemic lupus, cirrhosis of the liver, keloid formation, interstitial nephritis and pulmonary fibrosis.

The compounds of formula I can inhibit, in particular, the growth of malignant neoplasms, tumor cells and tumor metastases, and therefore suitable for the treatment of tumors.

In addition, the present invention relates to the use of compounds of the formula I and/or their physiologically acceptable salts and solvate for the preparation of a medicinal product for protection of normal cells against toxicity caused by chemotherapy, and for the treatment of diseases, the main cause is improper installation or aggregation of proteins such as, for example, prurigo, disease, Jakob-Creutzfeldt, Huntington's or Alzheimer's.

The invention also relates to the use of compounds of the formula I and/or their physiologically acceptable salts and solvate for the preparation of drugs for the treatment of diseases of the Central nervous system, cardiovascular system and cachexia.

In a further embodiment, the invention also relates to the use of compounds of the formula I and/or their physiologically acceptable salts and solvate for the preparation of drugs for the modulation of HSP90, where modulation of the biological activity of HSP90 cause an immune response in animals, transport of protein from the endoplasmic reticulum, recovery after hypoxic/anoxic stress, recovering from malnutrition, recovery from heat stress, or combinations thereof, and/or where the disease is a type of cancer, an infectious disease, a disorder associated with impaired transport of protein from the endoplasmic reticulum, a disorder associated with ischaemia/reperfusion, or combinations thereof, where a disorder associated with ischaemia/reperfusion, is a consequence of cardiac arrest, asistoliei and delayed ventricular fibrillation, heart surgery, heart surgery is but-pulmonary bypass, transplant, spinal cord injury, head trauma, stroke, thromboembolic stroke, hemorrhagic shock, spasm of cerebral vessels, hypotension, hypoglycaemia, epileptic condition, seizures, anxiety, schizophrenia, a neurodegenerative disorder, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) or neonatal stress.

In a further embodiment, the invention also relates to the use of compounds of the formula I and/or their physiologically acceptable salts and solvate for the preparation of drugs for the treatment of ischemia due to cardiac arrest, asystole and deferred fibrillation of ventricles, heart surgery, surgery, cardiopulmonary bypass surgery, organ transplants, spinal cord injuries, head trauma, stroke, thromboembolic stroke, hemorrhagic shock, spasm of cerebral vessels, hypotonia, hypoglycaemia, epileptic condition, epilepsy, anxiety, schizophrenia, neurodegenerative disorders, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) or neonatal stress.

Method of test to determine the effect of HSP90 inhibitors

Linking geldanamycin or 17 allylamino-17-demethoxygeldanamycin (17AAG) with HSP90 and its competitive Engibarov the tion can be used to determine the inhibitory effect of compounds in accordance with the invention (Carreras and others 2003, Chiosis and others 2002).

In the specific case, use the test binding of radioactively labeled ligand on the filter. Radioactively labeled ligand used in this test is a tritium-labeled 17-allylaminogeldanamycin, [3H]17AAG. This test is binding on the filter provides targeted search of inhibitors that interfere with ATP-binding site.

Materials

Recombinant human HSP90α (expressed E. coli, purity 95%);

[3H]17AAG (17-allylaminogeldanamycin, [allylamino-2,3-3N. The specific activity of 1.11×1012Bq/mmol (Moravek, MT-1717);

HEPES filtration buffer (50 mm HEPES, pH 7.0; 5 mm MgCl2, BSA 0,01%) Multiscreen FB (1 micron) filter tablet (Millipore, MAFBNOB 50).

Way

First microtiter filter plates 96-well watered, and covered with 0.1% polyethylenimine.

The study was carried out under the following conditions:

The reaction temperature 22°C

The reaction time is 30 min, shaking at 800 rpm

The test volume of 50 µl

Final concentration:

50 mm HEPES HCl, pH 7.0; 5 mm MgCl2; 0,01% (wt./about.) BSA

HSP90: 1.5 mcg/research

[3H]17AAG: 0,08 mm.

After the reaction, the supernatant in the filter plate was removed by suction using a vacuum installation (Multiscreen Separation System, Millipore) and the filter was washed two times.

Then filter plates were measured on metastatic (Microbeta, Wallac) with a scintillator (Microscint 20, Packard).

"% of control" was determined based on the values of "beats per minute" and they hoped IC-50 values for the connection.

When you specify above and below, all temperatures are indicated in degrees Celsius (°C). In the following examples normal "processing" means that, if necessary, water is added, pH is adjusted, if necessary, to a value from 2 to 10, depending on the composition of the end product, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate and evaporated, the product was then purified using chromatography on silica gel and/or crystallization. Rfvalues on silica gel; eluent: ethyl acetate/methanol 9:1.

Conditions LC-MS

HP 1100 series Hewlett Packard System that has the following characteristics: ion source: elektrorazpredelenie (positive mode); scan: 100-1000 m/e; voltage fragmentation 60 V; gas temperature of 300°C., DAD: 220 nm.

The flow rate of 2.4 ml/min is Used, the separator was reduced flow rate for MS to 0.75 ml/min, after DAD.

Column: Chromolith SpeedROD RP-18e 50-4,6

Solvent: LiChrosolv quality from Merck KGaA

Solvent A: H2O (0,01% TFU)

Solvent B: ACN (0,008% TFU)

Gradient:

20% B → 100% B: from 0 min to 2.8 minutes

100%: 2.8 min to 3.3 minutes

100% → 20% In: from 3.3 min to 4 min

Retention time Rf [min] and data MM M+N+specified in the following examples, were measured the results of LC-MS analyses.

Example 1

The General reaction scheme for producing compounds of the formula I, in which R2represents the acylated amino group:

Getting 2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(3-triphtalocyaninine)phenyl]thieno[2,3b]pyridine ("A1")

1.1 to 10.9 g cyanothioacetamide and 9 ml of 4-methylmorpholine was added to a solution of 10 g of 4-methoxy-3-nitrobenzaldehyde in 100 ml of ethanol and the mixture was stirred at room temperature for 48 hours. Was added 10% HCl to pH 5 and the mixture was stirred additionally for 16 hours. The precipitated substance was separated, washed with ethanol and n-heptane, and dried, obtaining 9.6 g of 6-amino-3,5-dicyano-4-(4-methoxy-3-nitrophenyl)-2-thioxo-1,2-dihydropyridines ("1")

.

1.2 One equivalent of KOH in water was added to a solution of 30.7 g of "1" in 100 ml of DMF. Then was added 8.8 g of 2-chloracetamide and the mixture was stirred additionally for one hour. Added additional equivalent of KOH in water and the mixture was stirred at room temperature for 16 hours, then at 100°C. additionally for one hour. The mixture was diluted with an equal amount of water, the precipitated substance was separated, washed with water and dried, obtaining 17 g of 2-aminocarb the Il-3,6-diamino-5-cyano-4-(4-methoxy-3-nitrophenyl)thieno[2,3-b]pyridine ("2").

1.3 1.8 to 2 in 100 ml of DMF was first made according to standard methods using 5% Pd/C (56% water) as a catalyst. After separation of the catalyst and removal of solvent received 2-aminocarbonyl-3,6-diamino-5-cyano-4-(3-amino-4-methoxyphenyl)thieno[2,3-b]pyridine ("3") in quantitative yield.

1H NMR 250 MHz, DMSO-6) δ 15,00 (b), a 7.62 (d, 1H), 7,51 (d, 1H), of 7.48 (d, 1H), 4,06 (s, 3H).

1.4 47 μl of 4-methylmorpholine was added to a solution of 45 μl of 3-(trifluoromethyl)benzoyl chloride and 48 mg hydrate of 1-hydroxybenzotriazole in 1 ml DMF and the mixture was stirred at room temperature for 1 hour. Added 100 mg of 3, and the mixture was stirred additionally for 16 hours. The mixture was stirred in 10 ml of water, precipitated substance was separated, washed with water and purified by chromatography (flash chromatography with reversed phase; Isco Companion®), receiving 24 mg A1, M+H+527,50

.

When carrying out a similar reaction "3"

acetylchloride,

triftoratsetilatsetonom,

chloride complex methyl ester of glutaric acid,

chloride 1H-pyridine-2-he-4-carboxylic acid,

4-methoxycarbonylbenzyl,

Methylchloroisothiazolinone,

3-triftormetilfullerenov

received connection

2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-acetamidophenyl)thieno[2,3-b]pyridine ("A2"), M+H+397,43;

Aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-Cryptor-acetamidophenyl)thieno[2,3-b]pyridine ("A3"), M+H+451,40;

2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-methoxy-carbonylation)phenyl]thieno[2,3-b]pyridine ("AA"),

2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(1H-pyridine-2-he-4-carbylamine)phenyl]thieno[2,3-b]pyridine ("A5"), M+N+476,49;

2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-methoxy-carbonylmethyl)phenyl]thieno[2,3-b]pyridine ("AA"),

2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(2-methoxycarbonylmethylene)phenyl]thieno[2,3-b]pyridine ("AA");

2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(3-triftormetilfullerenov)phenyl]thieno[2,3-b]pyridine ("A9"), M+N+563,55.

Example 2

During the hydrolysis of ester under standard conditions

"AA" received connection 2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-carboxymethylamino)phenyl]thieno[2,3-b]pyridine ("A4"), M+H+469,49;

"AA" received connection 2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-carboxymethylamino)phenyl]thieno[2,3-b]pyridine ("A6"), 10 M+H+503,51;

"AA" received connection 2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(2-carboxymethylamino)phenyl]thieno[2,3-b]pyridine ("A7"), M+H+471,46.

Example 3

82 mg of the hydrochloride of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (DAPECI) and 47 μl of 4-methylmorpholine was added to a solution of 55 mg of the BOC-glycine (BOC-Gly-OH) and 48 mg of hydrate of 1-hydroxybenzotriazole in 1 ml DMF and the MCA is ü stirred at room temperature for 1 hour. Added 100 mg of 3, and the mixture was stirred additionally for 16 hours. The mixture was stirred in 10 ml of water, precipitated substance was separated and washed with water, getting a 2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{2-[(tert-butyloxycarbonyl)amino]acetamido}phenyl)thieno[2,3-b]pyridine ("10"),

When carrying out a similar reaction "3"

BOC-β-Ala-OH (BOC-β-alanine),

BOC-GABA-OH (γ-aminobutyric acid),

1H-indole-7-carboxylic acid,

BOC-His-OH (BOC-histidine),

BOC-Asn-OH (BOC-asparagine),

N-(2-carbamoylethyl)glycine,

1H-indazol-7-carboxylic acid,

BOC-Ser(O-tert-butyl)-(BOC-(S)-serine tert-butyl ether)

received connection

2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{3-[(tert-butyl-oxycarbonyl)amino]propionamide}phenyl)thieno[2,3-b]pyridine ("A11"), M+H+526,59;

2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{4-[(tert-butyl-oxycarbonyl)amino]bucillamine}phenyl)thieno[2,3-b]pyridine ("And 12"), M+N+540,61;

2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(indol-7-yl-carbylamine)phenyl]thieno[2,3-b]pyridine ("A13"), M+H+498,54;

(S)-2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{2-[(tert-butyloxycarbonyl)amino]-3-(1H-imidazol-4-yl)propionamido}phenyl)thieno[2,3-b]pyridine ("AA"),

(S)-2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{2-[(tert-butyloxycarbonyl)amino]-3-is aminocarbonylmethyl}phenyl)thieno[2,3-b]pyridine ("AA"),

2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-[2-(2-carbamoylation)acetylamino]phenyl]thieno[2,3-b]pyridine ("A16"), M+H+497,51;

2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(indazol-7-ylcarbonyl)phenyl]thieno[2,3-b]pyridine ("A17"), M+H+499,52;

(S)-2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{2-[(tert-butyloxycarbonyl)amino]-3-(tert-Butylochka)propionamido}phenyl)thieno[2,3-b]pyridine ("AA").

Example 4

When removing the BOC protective groups

"A11",

"A12",

"AA",

"AA",

"AA"

and the cleavage of tert-butyl methyl ether in HCl/dioxane received connection

2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(3-amino-propionamido)phenyl]thieno[2,3-b]pyridine ("A21"),

2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-amino-Butylimino)phenyl]thieno[2,3-b]pyridine ("A22"), M+H+440,50;

(S)-2-aminocarbonyl-3,6-diamino-5-cyano-4-{4-methoxy-3-[2-amino-3-(1H-imidazol-4-yl)propionamido]phenyl}thieno[2,3-b]pyridine ("A14")

(S)-2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{2-amino-3-aminocarbonylmethyl}phenyl)thieno[2,3-b]pyridine ("A15"),

(S)-2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(2-amino-3-hydroxypropylamino)phenyl]thieno[2,3-b]pyridine ("A18").

Example 5

When carrying out the reaction of 2-aminocarbonyl-3,6-diamino-5-cyano-4-(2-amino-4-methoxyphenyl)thieno[2,3-b]pyridine (3A) with 3-triptime phenylisocyanate under standard conditions received connection 2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-2-(3-cryptomaterial)phenyl]thieno[2,3-b]pyridine ("A22").

Example 6

When carrying out the reaction of 2-aminocarbonyl-3,6-diamino-5-cyano-4-(2-amino-4-methoxyphenyl)thieno[2,3-b]pyridine (3A) analogously to example 1 with benzoyl chloride,

3-carbamoylphenoxy acid,

N-(phenylsulfonyl)glycine

received connection

2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-2-benzoylamine phenyl)thieno[2,3-b]pyridine ("A8"), M+H+459,50;

2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-2-(3-carbamoylbiphenyl)phenyl]thieno[2,3-b]pyridine ("A19"), M+H+454,48;

2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-2-[2-(phenyl-sulfonyl)acetylamino]phenyl]thieno[2,3-b]pyridine ("A20"), M+N+552,60.

Example 7

Getting 2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-2-[2-(3-ethylurea)ethylcarbamate]phenyl]thieno[2,3-b]pyridine ("A23")

7.1 reaction Scheme for obtaining predecessor "AA"

7.2 Mixture "A23a", "A23b"

,

the palladium (II) acetate (47% Pd), 1,8-diazabicyclo[5,4,0]undec-7-ene, THF and hexacarbonyl molybdenum irradiated by microwave for 1 hour at 120°C. When performing normal processing of received

2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-2-[2-(3-ethyl-ureido)ethylcarbamate]phenyl]thieno[2,3-b]pyridine ("A23"), M+H+497,55

.

When carrying out reactions

with a 7-aminoindazole the presence of Mo(CO) 6and Pd(OAc)2analogously to example 7,2 received connection

2-aminocarbonyl-3,6-diamino-5-cyano-4-[3-(indazol-7-ylcarbonyl)phenyl]thieno[2,3-b]pyridine ("A24"), M+H+469,50

.

When carrying out reactions

4-aminobutyrate in the presence of Mo(CO)6and Pd(OAc)2analogously to example 7,2 received connection

2-aminocarbonyl-3,6-diamino-5-cyano-4-[5-chloro-3-(3-carbarnoyl-propellerblades)phenyl]thieno[2,3-b]pyridine ("A25"), M+H+472,93

.

Example 8

PdCl2(dppf) was added to the bromide 3-tormentilla (0.5 M in THF) and the mixture was stirred at room temperature for 5 minutes in an argon atmosphere. Then was added dropwise a solution "AA"

in THF and the mixture was stirred at 45°C. additionally for 30 minutes, then at 65°C for 1 hour. The mixture was cooled, poured into saturated NH4Cl solution and subjected to conventional processing, receiving 2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(3-terbisil)phenyl]thieno[2,3-b]pyridine ("A26"), M+H+448,49

Example 9

9.1 Mixture AA"

,

2-vinylpyridine) - derivatives, triethylamine, palladium acetate (III) (47% Pd), tri-o-tolyl-phosphine and acetonitrile was irradiated with microwave at 160°C for 30 minutes. To the reaction the mixture was added toluene, which was extracted several times with water. The organic phase was dried and evaporated. The product was purified by chromatography (ISCO/40 g column; petroleum ether/ethyl acetate: 4/1 to 1/1)to give "A27b"

,

9.2 the Mixture A27b", 5% Pd/C (56% water) and THF was first made for 16 hours under a pressure of 1.4 bar at room temperature in a BÜCHI apparatus, removal of catalyst and solvent was removed, receiving 2-aminocarbonyl-3,6-diamino-5-cyano-4-{3-chloro-4-methoxy-2-[2-(pyridin-2-yl)ethyl]phenyl}thieno[2,3-b]pyridine ("A27"), M+H+497,96

When carrying out reactions "AA with methyl acrylate as in example 9.1 received connection AA"

and when it hydrogenation analogously to example 9.2 and the cleavage of ester was obtained connection

2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(2-carboxyethyl)phenyl]thieno[2,3-b]pyridine ("A28"), M+H+412,44

.

Example 10

The mixture AA", "AA"

,

propanol, palladium(II)acetate, triphenylphosphine, sodium carbonate solution and water was heated for 16 hours in an atmosphere of N2and in the flask with reflux condenser in the Suzuki reaction. The mixture was cooled, subjected to normal processing, when receiving the connection

2-aminocarbonyl-3,6-diamino-5-cyano-4-{4-methoxy-3-[2-(4-methylpiperazin--yl)ethoxy]phenyl}thieno[2,3-b]pyridine ("A29"), M+H+558,68

Example 11

When carrying out reactions "AA"

"A30b"

analogously to example 10 was obtained the compound 2-aminocarbonyl-3,6-diamino-5-cyano-4-{4-methoxy-3-[3-(2-aminoethylamino)phenyl]phenyl}thieno[2,3-b]pyridine ("A30"), M+H+559,66

Example 12

When carrying out reactions "A31a"

chloride methyl ester of glutaric acid analogously to example 1 got connection "A31b"

2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-chloro-2-(4-methoxycarbonylamino)phenyl]thieno[2,3-b]pyridine ("A31b").

The splitting of its complex ester was obtained 2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-chloro-2-(4-carboxymethylamino)phenyl]thieno[2,3-b]pyridine ("A31"), M+N+503,94

.

Example 13

When carrying out reactions "AA"

c "A32b"

analogously to example 1 got connection "A32" 2-aminocarbonyl-3,6-diamino-5-cyano-4-{2-chloro-4-deformedarse-3-[3-(4-methylpiperazin-1-yl)propionamido]phenyl}thieno[2,3-b]pyridine ("A32"), M+N+580,03

Example 14

When carrying out reactions "AA"

chloride marked the CSOs ester of glutaric acid analogously to example 1 got connection "A33b"

The splitting of its complex ester was obtained 2-(2-morpholine-4-iletileri)-3,6-diamino-5-cyano-4-[2-(4-carboxymethylamino)phenyl]thieno[2,3-b]pyridine ("A33"), M+N+552,63.

Example 15

When carrying out reactions "AA"

with benzyl alcohol under standard conditions received connection 2-aminocarbonyl-3,6-diamino-5-cyano-4-[2-(benzyloxycarbonylamino)phenyl]thieno[2,3-b]pyridine ("A34"), M+H+489,53 ("A34")

.

Example 16

The following compounds were obtained analogously to Receive "A1":

2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-Cryptor-methylbenzylamino)phenyl]thieno[2,3-b]pyridine ("A35"),

1H NMR 250 MHz, DMSO-d6) δ 9,99 (b), 8,16 (d, 1H), 7,92 (d, 2H), 7,37 (d, 2H), 7,02 (s, 1H), 5,90 (s, 1H), 3.96 points (s, 3H);

2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(2-Cryptor-methylbenzylamino)phenyl]thieno[2,3-b]pyridine ("A36").

Connection

2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(pyridin-4-yl-carbylamine)phenyl]thieno[2,3-b]pyridine ("A37"),

2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(prop-2-yl-carbylamine)phenyl]thieno[2,3-b]pyridine ("A38"),

received likewise Obtaining "And 17".

Pharmacological data

Affinity to the receptors shown in table 1.

Table1
No. of connectionsHSP90-IC50[M]
"A35"of 5.9×10-6
"A36"of 1.1×10-5
"A37"of 1.9×10-6
"A38"5,5×10-6

The examples below relate to pharmaceutical compositions.

Example: vials for injection

the pH of the solution to 100 g of the active component in accordance with the invention and 5 g of Na2HPO4in 3 l of bidistilled water was set at 6.5 using 2 N. hydrochloric acid, sterilized by filtration, transferred into vials for injection, liofilizirovanny under sterile conditions and sealed under sterile conditions. Each vial for injection contains 5 mg of the active component.

Example B: suppositories

A mixture of 20 g of the active component in accordance with the invention was melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and cooled. Each suppository contains 20 mg of the active component.

Example: solution

The solution is prepared from 1 g of the active component in accordance with the invention, 9,38 g NaH2PO4·2 H2O, 28,48 g Na2HPO4·12 H2O is 0.1 g benzylaniline in 940 ml of bidistilled water. the pH of the solution was set to 6.8, and the solution volume was brought to 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: ointment

500 mg of the active component in accordance with the invention was mixed with 99.5 g

vaseline under aseptic conditions.

Example D: tablets

A mixture of 1 kg of active component in accordance with the invention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate were compressed to obtain tablets in the usual way so that each tablet contained 10 mg of the active component.

Example E: bean

Tablets were pressed analogously to example E and are then coated in the usual way by a coating of sucrose, potato starch, talc, tragakant and dye.

Example G: capsules

2 kg of active component in accordance with the invention were placed in hard gelatin capsules in a conventional way so that each capsule contained 20 mg of the active component.

Example C: ampoules

A solution of 1 kg of active component in accordance with the invention in 60 l of bidistilled water were sterilized filtered, transferred into ampoules, liofilizirovanny under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of the active component.

Sources of informatsii

1. Compounds selected from the group including
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(3-trifluoromethyl benzoylamine)phenyl]thieno[2,3-b]pyridine ("A1"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-acetamidophenyl)thieno[2,3-b]pyridine ("A2"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-Cryptor-acetamido phenyl)thieno[2,3-b]pyridine ("A3"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-methoxycarbonylamino)phenyl]thieno[2,3-b]pyridine ("AA"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(1H-pyridine-2-he-4-carbylamine)phenyl]thieno[2,3-b]pyridine("A5"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-methoxycarbonyl benzoylamine)phenyl]thieno[2,3-b]pyridine ("AA"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(2-methoxycarbonyl methoxyacetate)phenyl]thieno[2,3-b]pyridine ("AA"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(3-triftormetilfullerenov)phenyl]thieno[2,3-b]pyridine ("A9"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-carboxymethylamino)phenyl]thieno[2,3-b]pyridine ("A4"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-carboxybenzoyl amino)phenyl]thieno[2,3-b]pyridine ("A6"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(2-ka is oximeters acetamido)phenyl]thieno[2,3-b]pyridine ("A7"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{2-[(tert-butyloxycarbonyl)amino]acetamido}phenyl)thieno[2,3-b]pyridine ("a10"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{3-[(tert-butyloxycarbonyl)amino]propionamide}phenyl)thieno[2,3-b]pyridine ("A11"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{4-[(tert-butyloxycarbonyl)amino]bucillamine}phenyl)thieno[2,3-b]pyridine ("A12"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(indol-7-ylcarbonyl)phenyl]thieno[2,3-b]pyridine ("A13"),
(S)-2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-3-{2-[(tert-butyloxycarbonyl)amino]-3-aminocarbonylmethyl}-phenyl)thieno[2,3-b]pyridine ("AA"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-[2-(2-carbamoylation)acetylamino]phenyl]thieno[2,3-b]pyridine ("A16"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(indazol-7-ylcarbonyl)phenyl]thieno[2,3-b]pyridine ("A17"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-amino-Butylimino)phenyl]thieno[2,3-b]pyridine ("A22"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-(4-methoxy-2-benzoyl-AMINOPHENYL)thieno[2,3-b]pyridine ("A8"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-2-(3-carbarnoyl, propionamido)phenyl]thieno[2,3-b]pyridine ("A19"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-2-[2-(phenyl sulfonyl)acetylamino]phenyl]thieno[2,3-b]pyridine ("A20"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-2-[2-(3-ethylurea) ethylcarbamate is]phenyl]thieno[2,3-b]pyridine ("A23"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[3-(indazol-7-ylcarbonyl)phenyl]thieno[2,3-b]pyridine ("A24"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[5-chloro-3-(3-carbamoylbiphenyl)phenyl]thieno[2,3-b]pyridine ("A25"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(3-terbisil)phenyl]thieno[2,3-b]pyridine ("A26"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-{3-chloro-4-methoxy-2-[2-(pyridin-2-yl)ethyl]phenyl}thieno[2,3-b]pyridine ("A27"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(2-carboxyethyl)phenyl]thieno[2,3-b]pyridine ("A28"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-{4-methoxy-3-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}thieno[2,3-b]pyridine ("A29"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-{4-methoxy-3-[3-(2-aminoethylamino)phenyl]phenyl}thieno[2,3-b]pyridine ("A30"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-chloro-2-(4-carboxymethylamino)phenyl]thieno[2,3-b]pyridine ("A31"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-{2-chloro-4-debtor-methoxy-3-[3-(4-methylpiperazin-1-yl)propionamido]phenyl}thieno-[2,3-b]pyridine ("A32"),
2-(2-morpholine-4-iletileri)-3,6-diamino-5-cyano-4-[2-(4-carboxymethylamino)phenyl]thieno[2,3-b]pyridine ("A33"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[2-(benzyloxycarbonylamino)phenyl]thieno[2,3-b]pyridine ("A34"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(4-triphtalocyaninine)phenyl]thieno[2,3-b]pyridine ("A35"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(2-triphtalocyaninine)phenyl]is ieno[2,3-b]pyridine ("A36"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(pyridine-4-ylcarbonyl)phenyl]thieno[2,3-b]pyridine ("A37"),
2-aminocarbonyl-3,6-diamino-5-cyano-4-[4-methoxy-3-(prop-2-ylcarbonyl)phenyl]thieno[2,3-b]pyridine ("A38"),
and their pharmaceutically suitable salts.

2. Drugs having inhibitory activity against HSP90 containing at least one compound according to claim 1 and/or pharmaceutically usable salt, and optionally excipients and/or auxiliary substances.

3. The use of compounds according to claim 1 and their pharmaceutically suitable salts for the preparation of medicines intended for the treatment and/or prevention of diseases which are influenced by inhibition, regulation and/or modulation of HSP90.



 

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24 cl, 75 ex, 290 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula I. In general formula I A is C or N; B, D and E independently represent CR4, NR5, N, O or S; and a ring containing groups A, B, D, E, selected from thienyl, furan, imidazole, oxazole, isothiazole, thiazole, pyrrol, pyrazole; provided that: b) when A is N, not any of B, D, E can be O or S; and c) when A is C, B is CR4 and one of D or E is N or NR5, when any of D or E cannot be NR5 or N; G is N or C; R1 represents one or more substitutes selected from H, Ra halogen, -OH and -ORa; R2 represents one or more substitutes selected from H, halogen and C1-6-alkyl, and also one of substitutes R2 can be -ORb' , -NRb' Rb', -SRb', -SORb', -SO2Rb', -SO2NRb' Rb'; R3 is H, or Cy, selected from phenyl optionally substituted with one or more substitutes selected from Rc , where Rc independently represents halogen, -ORg', where Rg' independently represents a Rg group, where Rg is C1-6-alkyl; each R4 independently represents H, Re, halogen, -CORe', -CO2Re', -CONRe'Re', -NRe'Re'; R5 independently represents H, Re, -CORe, -CONReRe, -SORe or -SO2Re; each Ra independently represents C1-6-alkyl or halogen- C1-6-alkyl; each R independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rb' independently represents H or Rb; each Rc independently represents halogen, -ORg', -CONRg'Rg', -NRg'Rg'; Rd is Cy optionally substituted with one or more Rf substitutes; each Rc independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rc and Cy*, or Re is Cy, where any of the groups Cy or Cy* can optionally be substituted with one or more substitutes selected from Rc and Rg ; each Re' independently represents H or Re; each Rf independently represents a halogen, -ORh', -CO2Rh; each Rg independently represents Rd or C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rg' independently represents H or Rg; each Rh independently represents C1-6-alkyl, halogen-C1-6-alkyl or hydroxy- C1-6-alkyl; each Rh' independently represents H or Rh; and Cy or Cy* given in definitions above is a partially saturated, saturated or aromatic 3-7-member monocyclic carbocyclic ring which optionally contains 1-2 heteroatoms selected from N and O, and where the ring or rings can be bonded to the remaining part of the molecule through a carbon or nitrogen atom.

EFFECT: obtaining formula I compounds with p38-kinase inhibitory properties which can be used in making drugs for treating such diseases as tumour immune and autoimmune diseases etc.

21 cl, 10 dwg, 8 tbl, 57 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , where R1 is C1-C7-alkyl; R2 is C1-C7-alkyl, C1-C7-haloalkyl, C3-C8-cycloalkyl; R3 is -NRaRb; possibly substituted phenyl, thiophenyl, furanyl, where the substitutes are selected from a group consisting of halogen, C1-C7-alkoxy, C1-C7-alkylsulphonyl and -C(O)O-C1-C7-alkyl; R4 is hydrogen or C1-C7-alkyl; R5 is hydrogen, halogen, C1-C7-alkyl, phenyl; or R5 together with R4 can form a ring selected from a group consisting of C5-C7-cycloalkyl, tetrahydrofuranyl, piperidine, tetrahydropyran, phenyl or pyridinyl, which can possibly be substituted with -C(O)O-C1-C7-alkyl; Ra and Rb together with the nitrogen atom to which they are bonded form piperidine; and to pharmaceutically acceptable salts thereof. The invention also relates to a medicinal agent based on the said compounds which has GABA-B receptor allosteric enhancement effect.

EFFECT: obtaining novel compounds and a medicinal agent based on the said compounds, which can be used in medicine for treating central nervous system disorders.

13 cl, 42 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula or pharmaceutically acceptable salt thereof; where Q is selected from a group consisting of R1 denotes H; each R2 independently denotes ZR; each JQ independently denotes ZQ, MQ, (LQ)-ZQ or (XQ)-MQ; each LQ and XQ independently denotes C1-6alkyl, where each carbon of the alkyl group is independently substituted in up to 2 cases -NR-, -NHR-, -NRC(O)O-; where each XQ is independently and optionally substituted with 0-2 JXQ; each ZR and ZQ independently denotes H; a C1-6alkyl group, a 5-7-member saturated or completely unsaturated monocyclic ring, having 0-2 nitrogen atoms; or a 9-member saturated bicyclic ring system having 1 nitrogen atom; where each is ZQ independently and optionally substituted with 0-3 JZQ; MQ denotes halogen, CN or N(R)2; each JLQ, JXQ and JZQ independently denotes V, M, (LV)-V, (LM)-M, halogen, C1-3alkoxy; each R independently denotes H, C1-6alkyl group; each LV and LM independently denotes C1-6alkyl, interrupted in up to 1 case by -C(O)-; where each V independently denotes H; C1-6alkyl group, a 5-6-member saturated or completely unsaturated monocyclic ring; where each V is independently or optionally substituted with 0-1 JV; each JV denotes NH2; each M independently denotes halogen, OH, O(C1-6alkyl), NH2, provided that when R1 and R2 - H, Q is not The invention also relates to a composition based compounds of formula I, a method of inhibiting activity of Aurora B protein kinase, FLT-3 protein kinase, a method of treating a proliferative disorder, particularly leukaemia or lymphoma and a method of producing compounds of formula I.

EFFECT: novel benzimidazole derivatives are obtained, which can be used as inhibitors of protein kinase Aurora B and FLT-3.

28 cl, 2 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds described by formula in which radical and symbol values are specified in the patent claim, and their pharmaceutically acceptable salts. These compounds inhibit tompomyosine-related kinases (Trk), and can find application in treating a malignant growth, such as breast cancer, rectal cancer and prostate cancer. Also, the invention relates to a method for producing these compounds, a based pharmaceutical composition and to methods of application thereof.

EFFECT: preparation of the pharmaceutical composition which can find application in treating a malignant growth.

18 cl, 134 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing N-{5-[4-(4-methyl piperazinomethyl)benzoylamido]-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula (I) (Imatibin) in form of a free base or acid addition salt. Said compounds have anti-tumour activity and can be used, for example, when treating leukaemia. The method involves reduction of N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula (IV) in the presence of a chemical reducing agent, reaction of the obtained N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula (II) with a dihydro-halide salt of 4-(4-methylpiperazinomethyl)benzoylhalide of formula (III) in the presence of an inert organic solvent which is not a base-acid acceptor to obtain a hydro-halide salt of imitinib of formula (I), where n equals 1, 2 or 3 and Hal denotes bromine, chlorine, fluorine or iodine in hydrated form, which, if needed, optionally undergoes further conversion to a free base or some other acid addition salt.

EFFECT: method simplifies the production and extraction process, the process takes place under mild conditions, the obtained hydrohalide salt of imatibin is virtually not soluble in organic solvents and can be easily extracted from the reaction mass.

39 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing N-{5-[4-(4-methyl piperazinomethyl)benzoylamido]-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula (I) (Imatibin) in form of a free base or acid addition salt. Said compounds have anti-tumour activity and can be used, for example, when treating leukaemia. The method involves reduction of N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula (IV) in the presence of a chemical reducing agent, reaction of the obtained N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula (II) with a dihydro-halide salt of 4-(4-methylpiperazinomethyl)benzoylhalide of formula (III) in the presence of an inert organic solvent which is not a base-acid acceptor to obtain a hydro-halide salt of imitinib of formula (I), where n equals 1, 2 or 3 and Hal denotes bromine, chlorine, fluorine or iodine in hydrated form, which, if needed, optionally undergoes further conversion to a free base or some other acid addition salt.

EFFECT: method simplifies the production and extraction process, the process takes place under mild conditions, the obtained hydrohalide salt of imatibin is virtually not soluble in organic solvents and can be easily extracted from the reaction mass.

39 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new cyclopenta[b]benzofuranyl derivatives of formula wherein substitutes R1, R2, R3, R4, R5, R6 and R7 and n are specified in the patent clam. These compounds exhibit properties of NF-kB-activity and/or AP-1 inhibitor/modulator. Also, the inventive subject matter are methods for preparing intermediate compounds thereof, a pharmaceutical composition containing them, administration thereof for prevention and/or treatment of inflammatory and autoimmune diseases, neurodegenerative diseases and hyperproliferative diseases caused by NF-kB- and/or AP-1-activity, and a method for prevention and/or treatment of said diseases.

EFFECT: preparation of new cyclopenta[b]benzofuranyl derivatives.

21 cl, 3 tbl, 151 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: real invention relates to field of pharmaceutics and medicine and deals with application of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-[5-(4-methyl-1H-imidazole-1-yl)-3-(trifluoromethyl)phenyl]benzamide or its N-oxide, or its pharmaceutically acceptable salt for obtaining medication, intended for treatment of myeloproliferative disease, caused by FIPILI-PDGFRα or TEL-PDGFRβ.

EFFECT: invention ensures increase of treatment efficiency.

11 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medications and deals with reinforcing agent for radiation therapy, which includes as active ingredient pyridine derivative, represented by general formula (1). Invention also relates to application of pyridine derivative, represented by general formula where R1, R2, R3 and R4 have values given in the formula, for obtaining reinforcing agent for radiation therapy and method of radio-therapy of cancer.

EFFECT: application of claimed reinforcing agent for radio-therapy makes it possible to reduce radiation dose and unfavorable side effects when applied in combination with cancer radio-therapy.

15 cl, 4 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly oncology, and can be applied in treating rectal cancer. A method involves radiation teletherapy, drug therapy (capecitabine, oxaliplatin), local UHF hyperthermia, metronidazole as a part of a composite mixture introduced through rectum, and following surgery. Capecitabine is introduced orally in dose 650 mg/m2 during the whole course of radiation therapy every 12 hours, oxaliplatin is administered on the 2nd, 9th, 16th days of treatment intravenously in dose 50 mg/m2. Local UHF hyperthermia precedes a radiation session on the 8th, 12th, 15th, 17th days of treatment. Radiation is executed at 4 Gy of single basic dose three times a week every 48 hours for 22 days, 40 Gy of total basic dose. Metronidazole as a part of a polymeric composition is introduced on 12th and 17th days of treatment before UHF hyperthermia sessions with exposition 5 hours. The treatment is carried out with underlying protection of surrounding tissues with gas hypoxic mixture GHM-9.

EFFECT: use of the invention allows reaching tumour regress and executing radical surgery due to a synergic effect of the components and an intensified therapeutic effect ensured by implemented mechanisms of radio- and chemosensibilisation.

2 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and pharmaceutical industry, namely to a composition containing acetocyclopropyl-taxotere and Trastuzumab used for treating breast cancer, for treating taxoid resistant cancer types.

EFFECT: preparation of the pharmaceutical composition for treating breast cancer.

2 cl, 1 tbl

Anticancer drug // 2414920

FIELD: medicine.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, namely to development of an anticancer drug. The anticancer drug exhibiting HT-29 and DLD-1 bowel cancer cell activity is presented by a dry extract of Amur maackia heartwood.

EFFECT: drug extends the range of anticancer agents active in relation to HT-29 and DLD-1 bowel cancer cells.

3 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to application in an effective amount and to new nicotine receptor agonists described by general formula (i) or (ii) for treating inflammatory diseases chosen from a group including asthma, chronic obstructive pulmonary disease (COPD), interstitial pulmonary tissue fibrosis (IPF), sarcoidosis, hypersensitivity pneumonitis (HP), chronic hypersensitivity pneumonitis and bronchiolitis obliterans organising pneumonia (BOOP). The compounds (i) and compounds (ii) relate to formulae (i) (ii) where in formula (i) R1 and R2 independently mean alkyl with 1-10 carbon atoms; Xa means CH or N; Ya means one or more substitutes chosen from hydrogen, halogen, cyano, hydroxyl, alkyl with 1-10 carbon atoms optionally substituted with one or more halogen atoms, and alkoxy with 1-10 carbon atoms; n means an integer 0 or 2; J means a counterion representing a compound for maintaining electric neutrality, e.g., halogen, sulphate, sulphonate; in formula (ii) R3 is chosen from or Xb means N or N+-R10; R4 means one or more substitutes chosen from hydrogen, halogen; each R10, R11 and R12 independently means alkyl with 1-10 carbon atoms; provided the presence of the counterion when Xb means N+-R10.

EFFECT: use of nicotine receptor agonists in the effective amount for treating inflammatory diseases.

26 cl, 40 dwg, 3 tbl, 38 ex

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